Daily Papers

Large Language Models (LLMs), with their remarkable task-handling capabilities and innovative outputs, have catalyzed significant advancements across a spectrum of fields. However, their proficiency within specialized domains such as biomolecular studies remains limited. To address this challenge, we introduce Mol-Instructions, a meticulously curated, comprehensive instruction dataset expressly designed for the biomolecular realm. Mol-Instructions is composed of three pivotal components: molecule-oriented instructions, protein-oriented instructions, and biomolecular text instructions, each curated to enhance the understanding and prediction capabilities of LLMs concerning biomolecular features and behaviors. Through extensive instruction tuning experiments on the representative LLM, we underscore the potency of Mol-Instructions to enhance the adaptability and cognitive acuity of large models within the complex sphere of biomolecular studies, thereby promoting advancements in the biomolecular research community. Mol-Instructions is made publicly accessible for future research endeavors and will be subjected to continual updates for enhanced applicability.

Current Large Language Models (LLMs) for understanding proteins primarily treats amino acid sequences as a text modality. Meanwhile, Protein Language Models (PLMs), such as ESM-2, have learned massive sequential evolutionary knowledge from the universe of natural protein sequences. Furthermore, structure-based encoders like ProteinMPNN learn the structural information of proteins through Graph Neural Networks. However, whether the incorporation of protein encoders can enhance the protein understanding of LLMs has not been explored. To bridge this gap, we propose EvoLlama, a multimodal framework that connects a structure-based encoder, a sequence-based protein encoder and an LLM for protein understanding. EvoLlama consists of a ProteinMPNN structure encoder, an ESM-2 protein sequence encoder, a multimodal projector to align protein and text representations and a Llama-3 text decoder. To train EvoLlama, we fine-tune it on protein-oriented instructions and protein property prediction datasets verbalized via natural language instruction templates. Our experiments show that EvoLlama's protein understanding capabilities have been significantly enhanced, outperforming other fine-tuned protein-oriented LLMs in zero-shot settings by an average of 1%-8% and surpassing the state-of-the-art baseline with supervised fine-tuning by an average of 6%. On protein property prediction datasets, our approach achieves promising results that are competitive with state-of-the-art task-specific baselines. We will release our code in a future version.

Large Language Models (LLMs) have revolutionized the field of natural language processing, but they fall short in comprehending biological sequences such as proteins. To address this challenge, we propose InstructProtein, an innovative LLM that possesses bidirectional generation capabilities in both human and protein languages: (i) taking a protein sequence as input to predict its textual function description and (ii) using natural language to prompt protein sequence generation. To achieve this, we first pre-train an LLM on both protein and natural language corpora, enabling it to comprehend individual languages. Then supervised instruction tuning is employed to facilitate the alignment of these two distinct languages. Herein, we introduce a knowledge graph-based instruction generation framework to construct a high-quality instruction dataset, addressing annotation imbalance and instruction deficits in existing protein-text corpus. In particular, the instructions inherit the structural relations between proteins and function annotations in knowledge graphs, which empowers our model to engage in the causal modeling of protein functions, akin to the chain-of-thought processes in natural languages. Extensive experiments on bidirectional protein-text generation tasks show that InstructProtein outperforms state-of-the-art LLMs by large margins. Moreover, InstructProtein serves as a pioneering step towards text-based protein function prediction and sequence design, effectively bridging the gap between protein and human language understanding.

Current AI-assisted protein design mainly utilizes protein sequential and structural information. Meanwhile, there exists tremendous knowledge curated by humans in the text format describing proteins' high-level properties. Yet, whether the incorporation of such text data can help protein design tasks has not been explored. To bridge this gap, we propose ProteinDT, a multi-modal framework that leverages textual descriptions for protein design. ProteinDT consists of three subsequent steps: ProteinCLAP that aligns the representation of two modalities, a facilitator that generates the protein representation from the text modality, and a decoder that generates the protein sequences from the representation. To train ProteinDT, we construct a large dataset, SwissProtCLAP, with 441K text and protein pairs. We empirically verify the effectiveness of ProteinDT from three aspects: (1) consistently superior performance on four out of six protein property prediction benchmarks; (2) over 90% accuracy for text-guided protein generation; and (3) promising results for zero-shot text-guided protein editing.

Proteins are essential macromolecules defined by their amino acid sequences, which determine their three-dimensional structures and, consequently, their functions in all living organisms. Therefore, generative protein modeling necessitates a multimodal approach to simultaneously model, understand, and generate both sequences and structures. However, existing methods typically use separate models for each modality, limiting their ability to capture the intricate relationships between sequence and structure. This results in suboptimal performance in tasks that requires joint understanding and generation of both modalities. In this paper, we introduce DPLM-2, a multimodal protein foundation model that extends discrete diffusion protein language model (DPLM) to accommodate both sequences and structures. To enable structural learning with the language model, 3D coordinates are converted to discrete tokens using a lookup-free quantization-based tokenizer. By training on both experimental and high-quality synthetic structures, DPLM-2 learns the joint distribution of sequence and structure, as well as their marginals and conditionals. We also implement an efficient warm-up strategy to exploit the connection between large-scale evolutionary data and structural inductive biases from pre-trained sequence-based protein language models. Empirical evaluation shows that DPLM-2 can simultaneously generate highly compatible amino acid sequences and their corresponding 3D structures eliminating the need for a two-stage generation approach. Moreover, DPLM-2 demonstrates competitive performance in various conditional generation tasks, including folding, inverse folding, and scaffolding with multimodal motif inputs, as well as providing structure-aware representations for predictive tasks.

Large language models have already demonstrated their formidable capabilities in general domains, ushering in a revolutionary transformation. However, exploring and exploiting the extensive knowledge of these models to comprehend multi-omics biology remains underexplored. To fill this research gap, we first introduce Biology-Instructions, the first large-scale multi-omics biological sequences-related instruction-tuning dataset including DNA, RNA, proteins, and multi-molecules, designed to bridge the gap between large language models (LLMs) and complex biological sequences-related tasks. This dataset can enhance the versatility of LLMs by integrating diverse biological sequenced-based prediction tasks with advanced reasoning capabilities, while maintaining conversational fluency. Additionally, we reveal significant performance limitations in even state-of-the-art LLMs on biological sequence-related multi-omics tasks without specialized pre-training and instruction-tuning. We further develop a strong baseline called ChatMultiOmics with a novel three-stage training pipeline, demonstrating the powerful ability to understand biology by using Biology-Instructions. Biology-Instructions and ChatMultiOmics are publicly available and crucial resources for enabling more effective integration of LLMs with multi-omics sequence analysis.

Protein modeling is an increasingly popular area of machine learning research. Semi-supervised learning has emerged as an important paradigm in protein modeling due to the high cost of acquiring supervised protein labels, but the current literature is fragmented when it comes to datasets and standardized evaluation techniques. To facilitate progress in this field, we introduce the Tasks Assessing Protein Embeddings (TAPE), a set of five biologically relevant semi-supervised learning tasks spread across different domains of protein biology. We curate tasks into specific training, validation, and test splits to ensure that each task tests biologically relevant generalization that transfers to real-life scenarios. We benchmark a range of approaches to semi-supervised protein representation learning, which span recent work as well as canonical sequence learning techniques. We find that self-supervised pretraining is helpful for almost all models on all tasks, more than doubling performance in some cases. Despite this increase, in several cases features learned by self-supervised pretraining still lag behind features extracted by state-of-the-art non-neural techniques. This gap in performance suggests a huge opportunity for innovative architecture design and improved modeling paradigms that better capture the signal in biological sequences. TAPE will help the machine learning community focus effort on scientifically relevant problems. Toward this end, all data and code used to run these experiments are available at https://github.com/songlab-cal/tape.

We report a flexible language-model based deep learning strategy, applied here to solve complex forward and inverse problems in protein modeling, based on an attention neural network that integrates transformer and graph convolutional architectures in a causal multi-headed graph mechanism, to realize a generative pretrained model. The model is applied to predict secondary structure content (per-residue level and overall content), protein solubility, and sequencing tasks. Further trained on inverse tasks, the model is rendered capable of designing proteins with these properties as target features. The model is formulated as a general framework, completely prompt-based, and can be adapted for a variety of downstream tasks. We find that adding additional tasks yields emergent synergies that the model exploits in improving overall performance, beyond what would be possible by training a model on each dataset alone. Case studies are presented to validate the method, yielding protein designs specifically focused on structural proteins, but also exploring the applicability in the design of soluble, antimicrobial biomaterials. While our model is trained to ultimately perform 8 distinct tasks, with available datasets it can be extended to solve additional problems. In a broader sense, this work illustrates a form of multiscale modeling that relates a set of ultimate building blocks (here, byte-level utf8 characters) to complex output. This materiomic scheme captures complex emergent relationships between universal building block and resulting properties via a synergizing learning capacity to express a set of potentialities embedded in the knowledge used in training, via the interplay of universality and diversity.

Protein language models are a powerful tool for learning protein representations through pre-training on vast protein sequence datasets. However, traditional protein language models lack explicit structural supervision, despite its relevance to protein function. To address this issue, we introduce the integration of remote homology detection to distill structural information into protein language models without requiring explicit protein structures as input. We evaluate the impact of this structure-informed training on downstream protein function prediction tasks. Experimental results reveal consistent improvements in function annotation accuracy for EC number and GO term prediction. Performance on mutant datasets, however, varies based on the relationship between targeted properties and protein structures. This underscores the importance of considering this relationship when applying structure-aware training to protein function prediction tasks. Code and model weights are available at https://github.com/DeepGraphLearning/esm-s.

This paper demonstrates that language models are strong structure-based protein designers. We present LM-Design, a generic approach to reprogramming sequence-based protein language models (pLMs), that have learned massive sequential evolutionary knowledge from the universe of natural protein sequences, to acquire an immediate capability to design preferable protein sequences for given folds. We conduct a structural surgery on pLMs, where a lightweight structural adapter is implanted into pLMs and endows it with structural awareness. During inference, iterative refinement is performed to effectively optimize the generated protein sequences. Experiments show that LM-Design improves the state-of-the-art results by a large margin, leading to up to 4% to 12% accuracy gains in sequence recovery (e.g., 55.65%/56.63% on CATH 4.2/4.3 single-chain benchmarks, and >60% when designing protein complexes). We provide extensive and in-depth analyses, which verify that LM-Design can (1) indeed leverage both structural and sequential knowledge to accurately handle structurally non-deterministic regions, (2) benefit from scaling data and model size, and (3) generalize to other proteins (e.g., antibodies and de novo proteins)

The complex nature of big biological systems pushed some scientists to classify its understanding under the inconceivable missions. Different leveled challenges complicated this task, one of is the prediction of a protein's function. In recent years, significant progress has been made in this field through the development of various machine learning approaches. However, most existing methods formulate the task as a multi-classification problem, i.e assigning predefined labels to proteins. In this work, we propose a novel approach, Prot2Text, which predicts a protein function's in a free text style, moving beyond the conventional binary or categorical classifications. By combining Graph Neural Networks(GNNs) and Large Language Models(LLMs), in an encoder-decoder framework, our model effectively integrates diverse data types including proteins' sequences, structures, and textual annotations. This multimodal approach allows for a holistic representation of proteins' functions, enabling the generation of detailed and accurate descriptions. To evaluate our model, we extracted a multimodal protein dataset from SwissProt, and demonstrate empirically the effectiveness of Prot2Text. These results highlight the transformative impact of multimodal models, specifically the fusion of GNNs and LLMs, empowering researchers with powerful tools for more accurate prediction of proteins' functions. The code, the models and a demo will be publicly released.

Motivation: The development of novel compounds targeting proteins of interest is one of the most important tasks in the pharmaceutical industry. Deep generative models have been applied to targeted molecular design and have shown promising results. Recently, target-specific molecule generation has been viewed as a translation between the protein language and the chemical language. However, such a model is limited by the availability of interacting protein-ligand pairs. On the other hand, large amounts of unlabeled protein sequences and chemical compounds are available and have been used to train language models that learn useful representations. In this study, we propose exploiting pretrained biochemical language models to initialize (i.e. warm start) targeted molecule generation models. We investigate two warm start strategies: (i) a one-stage strategy where the initialized model is trained on targeted molecule generation (ii) a two-stage strategy containing a pre-finetuning on molecular generation followed by target specific training. We also compare two decoding strategies to generate compounds: beam search and sampling. Results: The results show that the warm-started models perform better than a baseline model trained from scratch. The two proposed warm-start strategies achieve similar results to each other with respect to widely used metrics from benchmarks. However, docking evaluation of the generated compounds for a number of novel proteins suggests that the one-stage strategy generalizes better than the two-stage strategy. Additionally, we observe that beam search outperforms sampling in both docking evaluation and benchmark metrics for assessing compound quality. Availability and implementation: The source code is available at https://github.com/boun-tabi/biochemical-lms-for-drug-design and the materials are archived in Zenodo at https://doi.org/10.5281/zenodo.6832145

This paper introduces diffusion protein language model (DPLM), a versatile protein language model that demonstrates strong generative and predictive capabilities for protein sequences. We first pre-train scalable DPLMs from evolutionary-scale protein sequences within a generative self-supervised discrete diffusion probabilistic framework, which generalizes language modeling for proteins in a principled way. After pre-training, DPLM exhibits the ability to generate structurally plausible, novel, and diverse protein sequences for unconditional generation. We further demonstrate the proposed diffusion generative pre-training makes DPLM possess a better understanding of proteins, making it a superior representation learner, which can be fine-tuned for various predictive tasks, comparing favorably to ESM2 (Lin et al., 2022). Moreover, DPLM can be tailored for various needs, which showcases its prowess of conditional generation in several ways: (1) conditioning on partial peptide sequences, e.g., generating scaffolds for functional motifs with high success rate; (2) incorporating other modalities as conditioner, e.g., structure-conditioned generation for inverse folding; and (3) steering sequence generation towards desired properties, e.g., satisfying specified secondary structures, through a plug-and-play classifier guidance. Code is released at https://github.com/bytedance/dplm.

Learning effective protein representations is critical in a variety of tasks in biology such as predicting protein function or structure. Existing approaches usually pretrain protein language models on a large number of unlabeled amino acid sequences and then finetune the models with some labeled data in downstream tasks. Despite the effectiveness of sequence-based approaches, the power of pretraining on known protein structures, which are available in smaller numbers only, has not been explored for protein property prediction, though protein structures are known to be determinants of protein function. In this paper, we propose to pretrain protein representations according to their 3D structures. We first present a simple yet effective encoder to learn the geometric features of a protein. We pretrain the protein graph encoder by leveraging multiview contrastive learning and different self-prediction tasks. Experimental results on both function prediction and fold classification tasks show that our proposed pretraining methods outperform or are on par with the state-of-the-art sequence-based methods, while using much less pretraining data. Our implementation is available at https://github.com/DeepGraphLearning/GearNet.

Generative machine learning models are increasingly being used to design novel proteins for therapeutic and biotechnological applications. However, the current methods mostly focus on the design of proteins with a fixed backbone structure, which leads to their limited ability to account for protein flexibility, one of the crucial properties for protein function. Learning to engineer protein flexibility is problematic because the available data are scarce, heterogeneous, and costly to obtain using computational as well as experimental methods. Our contributions to address this problem are three-fold. First, we comprehensively compare methods for quantifying protein flexibility and identify data relevant to learning. Second, we design and train flexibility predictors utilizing sequential or both sequential and structural information on the input. We overcome the data scarcity issue by leveraging a pre-trained protein language model. Third, we introduce a method for fine-tuning a protein inverse folding model to steer it toward desired flexibility in specified regions. We demonstrate that our method Flexpert-Design enables guidance of inverse folding models toward increased flexibility. This opens up new possibilities for protein flexibility engineering and the development of proteins with enhanced biological activities.

Protein language models have shown remarkable success in learning biological information from protein sequences. However, most existing models are limited by either autoencoding or autoregressive pre-training objectives, which makes them struggle to handle protein understanding and generation tasks concurrently. We propose a unified protein language model, xTrimoPGLM, to address these two types of tasks simultaneously through an innovative pre-training framework. Our key technical contribution is an exploration of the compatibility and the potential for joint optimization of the two types of objectives, which has led to a strategy for training xTrimoPGLM at an unprecedented scale of 100 billion parameters and 1 trillion training tokens. Our extensive experiments reveal that 1) xTrimoPGLM significantly outperforms other advanced baselines in 18 protein understanding benchmarks across four categories. The model also facilitates an atomic-resolution view of protein structures, leading to an advanced 3D structural prediction model that surpasses existing language model-based tools. 2) xTrimoPGLM not only can generate de novo protein sequences following the principles of natural ones, but also can perform programmable generation after supervised fine-tuning (SFT) on curated sequences. These results highlight the substantial capability and versatility of xTrimoPGLM in understanding and generating protein sequences, contributing to the evolving landscape of foundation models in protein science.

The integration of biomolecular modeling with natural language (BL) has emerged as a promising interdisciplinary area at the intersection of artificial intelligence, chemistry and biology. This approach leverages the rich, multifaceted descriptions of biomolecules contained within textual data sources to enhance our fundamental understanding and enable downstream computational tasks such as biomolecule property prediction. The fusion of the nuanced narratives expressed through natural language with the structural and functional specifics of biomolecules described via various molecular modeling techniques opens new avenues for comprehensively representing and analyzing biomolecules. By incorporating the contextual language data that surrounds biomolecules into their modeling, BL aims to capture a holistic view encompassing both the symbolic qualities conveyed through language as well as quantitative structural characteristics. In this review, we provide an extensive analysis of recent advancements achieved through cross modeling of biomolecules and natural language. (1) We begin by outlining the technical representations of biomolecules employed, including sequences, 2D graphs, and 3D structures. (2) We then examine in depth the rationale and key objectives underlying effective multi-modal integration of language and molecular data sources. (3) We subsequently survey the practical applications enabled to date in this developing research area. (4) We also compile and summarize the available resources and datasets to facilitate future work. (5) Looking ahead, we identify several promising research directions worthy of further exploration and investment to continue advancing the field. The related resources and contents are updating in https://github.com/QizhiPei/Awesome-Biomolecule-Language-Cross-Modeling.

Recent advancements in specialized large-scale architectures for training image and language have profoundly impacted the field of computer vision and natural language processing (NLP). Language models, such as the recent ChatGPT and GPT4 have demonstrated exceptional capabilities in processing, translating, and generating human languages. These breakthroughs have also been reflected in protein research, leading to the rapid development of numerous new methods in a short time, with unprecedented performance. Language models, in particular, have seen widespread use in protein research, as they have been utilized to embed proteins, generate novel ones, and predict tertiary structures. In this book chapter, we provide an overview of the use of protein generative models, reviewing 1) language models for the design of novel artificial proteins, 2) works that use non-Transformer architectures, and 3) applications in directed evolution approaches.

The parallels between protein sequences and natural language in their sequential structures have inspired the application of large language models (LLMs) to protein understanding. Despite the success of LLMs in NLP, their effectiveness in comprehending protein sequences remains an open question, largely due to the absence of datasets linking protein sequences to descriptive text. Researchers have then attempted to adapt LLMs for protein understanding by integrating a protein sequence encoder with a pre-trained LLM. However, this adaptation raises a fundamental question: "Can LLMs, originally designed for NLP, effectively comprehend protein sequences as a form of language?" Current datasets fall short in addressing this question due to the lack of a direct correlation between protein sequences and corresponding text descriptions, limiting the ability to train and evaluate LLMs for protein understanding effectively. To bridge this gap, we introduce ProteinLMDataset, a dataset specifically designed for further self-supervised pretraining and supervised fine-tuning (SFT) of LLMs to enhance their capability for protein sequence comprehension. Specifically, ProteinLMDataset includes 17.46 billion tokens for pretraining and 893,000 instructions for SFT. Additionally, we present ProteinLMBench, the first benchmark dataset consisting of 944 manually verified multiple-choice questions for assessing the protein understanding capabilities of LLMs. ProteinLMBench incorporates protein-related details and sequences in multiple languages, establishing a new standard for evaluating LLMs' abilities in protein comprehension. The large language model InternLM2-7B, pretrained and fine-tuned on the ProteinLMDataset, outperforms GPT-4 on ProteinLMBench, achieving the highest accuracy score. The dataset and the benchmark are available at https://huggingface.co/datasets/tsynbio/ProteinLMBench.

Large Language Models (LLMs), including GPT-x and LLaMA2, have achieved remarkable performance in multiple Natural Language Processing (NLP) tasks. Under the premise that protein sequences constitute the protein language, Protein Large Language Models (ProLLMs) trained on protein corpora excel at de novo protein sequence generation. However, as of now, unlike LLMs in NLP, no ProLLM is capable of multiple tasks in the Protein Language Processing (PLP) field. This prompts us to delineate the inherent limitations in current ProLLMs: (i) the lack of natural language capabilities, (ii) insufficient instruction understanding, and (iii) high training resource demands. To address these challenges, we introduce a training framework to transform any general LLM into a ProLLM capable of handling multiple PLP tasks. Specifically, our framework utilizes low-rank adaptation and employs a two-stage training approach, and it is distinguished by its universality, low overhead, and scalability. Through training under this framework, we propose the ProLLaMA model, the first known ProLLM to handle multiple PLP tasks simultaneously. Experiments show that ProLLaMA achieves state-of-the-art results in the unconditional protein sequence generation task. In the controllable protein sequence generation task, ProLLaMA can design novel proteins with desired functionalities. In the protein property prediction task, ProLLaMA achieves nearly 100\% accuracy across many categories. The latter two tasks are beyond the reach of other ProLLMs. Code is available at https://github.com/Lyu6PosHao/ProLLaMA.

Current protein language models (PLMs) learn protein representations mainly based on their sequences, thereby well capturing co-evolutionary information, but they are unable to explicitly acquire protein functions, which is the end goal of protein representation learning. Fortunately, for many proteins, their textual property descriptions are available, where their various functions are also described. Motivated by this fact, we first build the ProtDescribe dataset to augment protein sequences with text descriptions of their functions and other important properties. Based on this dataset, we propose the ProtST framework to enhance Protein Sequence pre-training and understanding by biomedical Texts. During pre-training, we design three types of tasks, i.e., unimodal mask prediction, multimodal representation alignment and multimodal mask prediction, to enhance a PLM with protein property information with different granularities and, at the same time, preserve the PLM's original representation power. On downstream tasks, ProtST enables both supervised learning and zero-shot prediction. We verify the superiority of ProtST-induced PLMs over previous ones on diverse representation learning benchmarks. Under the zero-shot setting, we show the effectiveness of ProtST on zero-shot protein classification, and ProtST also enables functional protein retrieval from a large-scale database without any function annotation.

The goal of protein representation learning is to extract knowledge from protein databases that can be applied to various protein-related downstream tasks. Although protein sequence, structure, and function are the three key modalities for a comprehensive understanding of proteins, existing methods for protein representation learning have utilized only one or two of these modalities due to the difficulty of capturing the asymmetric interrelationships between them. To account for this asymmetry, we introduce our novel asymmetric multi-modal masked autoencoder (AMMA). AMMA adopts (1) a unified multi-modal encoder to integrate all three modalities into a unified representation space and (2) asymmetric decoders to ensure that sequence latent features reflect structural and functional information. The experiments demonstrate that the proposed AMMA is highly effective in learning protein representations that exhibit well-aligned inter-modal relationships, which in turn makes it effective for various downstream protein-related tasks.

Learning effective protein representations is critical in a variety of tasks in biology such as predicting protein functions. Recent sequence representation learning methods based on Protein Language Models (PLMs) excel in sequence-based tasks, but their direct adaptation to tasks involving protein structures remains a challenge. In contrast, structure-based methods leverage 3D structural information with graph neural networks and geometric pre-training methods show potential in function prediction tasks, but still suffers from the limited number of available structures. To bridge this gap, our study undertakes a comprehensive exploration of joint protein representation learning by integrating a state-of-the-art PLM (ESM-2) with distinct structure encoders (GVP, GearNet, CDConv). We introduce three representation fusion strategies and explore different pre-training techniques. Our method achieves significant improvements over existing sequence- and structure-based methods, setting new state-of-the-art for function annotation. This study underscores several important design choices for fusing protein sequence and structure information. Our implementation is available at https://github.com/DeepGraphLearning/ESM-GearNet.

Self-supervised training of language models (LMs) has seen great success for protein sequences in learning meaningful representations and for generative drug design. Most protein LMs are based on the Transformer architecture trained on individual proteins with short context lengths. Such protein LMs cannot extrapolate to longer proteins and protein complexes well. They also fail to account for the underlying biological mechanisms carried out by biomolecular interactions and dynamics i.e., proteins often interact with other proteins, molecules, and pathways in complex biological systems. In this work, we propose LC-PLM based on an alternative protein LM architecture, BiMamba-S, built off selective structured state-space models, to learn high-quality universal protein representations at the amino acid token level using masked language modeling. We also introduce its graph-contextual variant, LC-PLM-G, which contextualizes protein-protein interaction (PPI) graphs for a second stage of training. LC-PLM demonstrates favorable neural scaling laws, better length extrapolation capability, and a 7% to 34% improvement on protein downstream tasks than Transformer-based ESM-2. LC-PLM-G further trained within the context of PPI graphs shows promising results on protein structure and function prediction tasks. Our study demonstrates the benefit of increasing the context size with computationally efficient LM architecture (e.g. structured state space models) in learning universal protein representations and incorporating molecular interaction context contained in biological graphs.

Tandem mass spectrometry has played a pivotal role in advancing proteomics, enabling the analysis of protein composition in biological samples. Despite the development of various deep learning methods for identifying amino acid sequences (peptides) responsible for observed spectra, challenges persist in de novo peptide sequencing. Firstly, prior methods struggle to identify amino acids with post-translational modifications (PTMs) due to their lower frequency in training data compared to canonical amino acids, further resulting in decreased peptide-level identification precision. Secondly, diverse types of noise and missing peaks in mass spectra reduce the reliability of training data (peptide-spectrum matches, PSMs). To address these challenges, we propose AdaNovo, a novel framework that calculates conditional mutual information (CMI) between the spectrum and each amino acid/peptide, using CMI for adaptive model training. Extensive experiments demonstrate AdaNovo's state-of-the-art performance on a 9-species benchmark, where the peptides in the training set are almost completely disjoint from the peptides of the test sets. Moreover, AdaNovo excels in identifying amino acids with PTMs and exhibits robustness against data noise. The supplementary materials contain the official code.

Transformer architectures have proven to learn useful representations for protein classification and generation tasks. However, these representations present challenges in interpretability. In this work, we demonstrate a set of methods for analyzing protein Transformer models through the lens of attention. We show that attention: (1) captures the folding structure of proteins, connecting amino acids that are far apart in the underlying sequence, but spatially close in the three-dimensional structure, (2) targets binding sites, a key functional component of proteins, and (3) focuses on progressively more complex biophysical properties with increasing layer depth. We find this behavior to be consistent across three Transformer architectures (BERT, ALBERT, XLNet) and two distinct protein datasets. We also present a three-dimensional visualization of the interaction between attention and protein structure. Code for visualization and analysis is available at https://github.com/salesforce/provis.

We introduce a protein language model for determining the complete sequence of a peptide based on measurement of a limited set of amino acids. To date, protein sequencing relies on mass spectrometry, with some novel edman degregation based platforms able to sequence non-native peptides. Current protein sequencing techniques face limitations in accurately identifying all amino acids, hindering comprehensive proteome analysis. Our method simulates partial sequencing data by selectively masking amino acids that are experimentally difficult to identify in protein sequences from the UniRef database. This targeted masking mimics real-world sequencing limitations. We then modify and finetune a ProtBert derived transformer-based model, for a new downstream task predicting these masked residues, providing an approximation of the complete sequence. Evaluating on three bacterial Escherichia species, we achieve per-amino-acid accuracy up to 90.5% when only four amino acids ([KCYM]) are known. Structural assessment using AlphaFold and TM-score validates the biological relevance of our predictions. The model also demonstrates potential for evolutionary analysis through cross-species performance. This integration of simulated experimental constraints with computational predictions offers a promising avenue for enhancing protein sequence analysis, potentially accelerating advancements in proteomics and structural biology by providing a probabilistic reconstruction of the complete protein sequence from limited experimental data.

Recent AI advances have enabled multi-modal systems to model and translate diverse information spaces. Extending beyond text and vision, we introduce OneProt, a multi-modal AI for proteins that integrates structural, sequence, alignment, and binding site data. Using the ImageBind framework, OneProt aligns the latent spaces of modality encoders along protein sequences. It demonstrates strong performance in retrieval tasks and surpasses state-of-the-art methods in various downstream tasks, including metal ion binding classification, gene-ontology annotation, and enzyme function prediction. This work expands multi-modal capabilities in protein models, paving the way for applications in drug discovery, biocatalytic reaction planning, and protein engineering.

Pre-trained LLMs have demonstrated substantial capabilities across a range of conventional natural language processing (NLP) tasks, such as summarization and entity recognition. In this paper, we explore the application of LLMs in the generation of high-quality protein sequences. Specifically, we adopt a suite of pre-trained LLMs, including Mistral-7B1, Llama-2-7B2, Llama-3-8B3, and gemma-7B4, to produce valid protein sequences. All of these models are publicly available.5 Unlike previous work in this field, our approach utilizes a relatively small dataset comprising 42,000 distinct human protein sequences. We retrain these models to process protein-related data, ensuring the generation of biologically feasible protein structures. Our findings demonstrate that even with limited data, the adapted models exhibit efficiency comparable to established protein-focused models such as ProGen varieties, ProtGPT2, and ProLLaMA, which were trained on millions of protein sequences. To validate and quantify the performance of our models, we conduct comparative analyses employing standard metrics such as pLDDT, RMSD, TM-score, and REU. Furthermore, we commit to making the trained versions of all four models publicly available, fostering greater transparency and collaboration in the field of computational biology.

Ribosomally synthesized and post-translationally modified peptide (RiPP) biosynthetic enzymes often exhibit promiscuous substrate preferences that cannot be reduced to simple rules. Large language models are promising tools for predicting such peptide fitness landscapes. However, state-of-the-art protein language models are trained on relatively few peptide sequences. A previous study comprehensively profiled the peptide substrate preferences of LazBF (a two-component serine dehydratase) and LazDEF (a three-component azole synthetase) from the lactazole biosynthetic pathway. We demonstrated that masked language modeling of LazBF substrate preferences produced language model embeddings that improved downstream classification models of both LazBF and LazDEF substrates. Similarly, masked language modeling of LazDEF substrate preferences produced embeddings that improved the performance of classification models of both LazBF and LazDEF substrates. Our results suggest that the models learned functional forms that are transferable between distinct enzymatic transformations that act within the same biosynthetic pathway. Our transfer learning method improved performance and data efficiency in data-scarce scenarios. We then fine-tuned models on each data set and showed that the fine-tuned models provided interpretable insight that we anticipate will facilitate the design of substrate libraries that are compatible with desired RiPP biosynthetic pathways.

The effects of ligand binding on protein structures and their in vivo functions carry numerous implications for modern biomedical research and biotechnology development efforts such as drug discovery. Although several deep learning (DL) methods and benchmarks designed for protein-ligand docking have recently been introduced, to date no prior works have systematically studied the behavior of the latest docking and structure prediction methods within the broadly applicable context of (1) using predicted (apo) protein structures for docking (e.g., for applicability to new proteins); (2) binding multiple (cofactor) ligands concurrently to a given target protein (e.g., for enzyme design); and (3) having no prior knowledge of binding pockets (e.g., for generalization to unknown pockets). To enable a deeper understanding of docking methods' real-world utility, we introduce PoseBench, the first comprehensive benchmark for broadly applicable protein-ligand docking. PoseBench enables researchers to rigorously and systematically evaluate DL methods for apo-to-holo protein-ligand docking and protein-ligand structure prediction using both primary ligand and multi-ligand benchmark datasets, the latter of which we introduce for the first time to the DL community. Empirically, using PoseBench, we find that (1) DL co-folding methods generally outperform comparable conventional and DL docking baselines, yet popular methods such as AlphaFold 3 are still challenged by prediction targets with novel protein sequences; (2) certain DL co-folding methods are highly sensitive to their input multiple sequence alignments, while others are not; and (3) DL methods struggle to strike a balance between structural accuracy and chemical specificity when predicting novel or multi-ligand protein targets. Code, data, tutorials, and benchmark results are available at https://github.com/BioinfoMachineLearning/PoseBench.

Understanding biological processes, drug development, and biotechnological advancements requires detailed analysis of protein structures and sequences, a task in protein research that is inherently complex and time-consuming when performed manually. To streamline this process, we introduce ProteinGPT, a state-of-the-art multi-modal protein chat system, that allows users to upload protein sequences and/or structures for comprehensive protein analysis and responsive inquiries. ProteinGPT seamlessly integrates protein sequence and structure encoders with linear projection layers for precise representation adaptation, coupled with a large language model (LLM) to generate accurate and contextually relevant responses. To train ProteinGPT, we construct a large-scale dataset of 132,092 proteins with annotations, and optimize the instruction-tuning process using GPT-4o. This innovative system ensures accurate alignment between the user-uploaded data and prompts, simplifying protein analysis. Experiments show that ProteinGPT can produce promising responses to proteins and their corresponding questions.

Proteins are essential to life's processes, underpinning evolution and diversity. Advances in sequencing technology have revealed millions of proteins, underscoring the need for sophisticated pre-trained protein models for biological analysis and AI development. Facebook's ESM2, the most advanced protein language model to date, leverages a masked prediction task for unsupervised learning, crafting amino acid representations with notable biochemical accuracy. Yet, it lacks in delivering functional protein insights, signaling an opportunity for enhancing representation quality.Our study addresses this gap by incorporating protein family classification into ESM2's training.This approach, augmented with Community Propagation-Based Clustering Algorithm, improves global protein representations, while a contextual prediction task fine-tunes local amino acid accuracy. Significantly, our model achieved state-of-the-art results in several downstream experiments, demonstrating the power of combining global and local methodologies to substantially boost protein representation quality.

Understanding the 3D structures of protein multimers is crucial, as they play a vital role in regulating various cellular processes. It has been empirically confirmed that the multimer structure prediction~(MSP) can be well handled in a step-wise assembly fashion using provided dimer structures and predicted protein-protein interactions~(PPIs). However, due to the biological gap in the formation of dimers and larger multimers, directly applying PPI prediction techniques can often cause a poor generalization to the MSP task. To address this challenge, we aim to extend the PPI knowledge to multimers of different scales~(i.e., chain numbers). Specifically, we propose \textsc{PromptMSP}, a pre-training and Prompt tuning framework for Multimer Structure Prediction. First, we tailor the source and target tasks for effective PPI knowledge learning and efficient inference, respectively. We design PPI-inspired prompt learning to narrow the gaps of two task formats and generalize the PPI knowledge to multimers of different scales. We provide a meta-learning strategy to learn a reliable initialization of the prompt model, enabling our prompting framework to effectively adapt to limited data for large-scale multimers. Empirically, we achieve both significant accuracy (RMSD and TM-Score) and efficiency improvements compared to advanced MSP models. The code, data and checkpoints are released at https://github.com/zqgao22/PromptMSP.

Protein function prediction is a crucial task in bioinformatics, with significant implications for understanding biological processes and disease mechanisms. While the relationship between sequence and function has been extensively explored, translating protein structure to function continues to present substantial challenges. Various models, particularly, CNN and graph-based deep learning approaches that integrate structural and functional data, have been proposed to address these challenges. However, these methods often fall short in elucidating the functional significance of key residues essential for protein functionality, as they predominantly adopt a retrospective perspective, leading to suboptimal performance. Inspired by region proposal networks in computer vision, we introduce the Protein Region Proposal Network (ProteinRPN) for accurate protein function prediction. Specifically, the region proposal module component of ProteinRPN identifies potential functional regions (anchors) which are refined through the hierarchy-aware node drop pooling layer favoring nodes with defined secondary structures and spatial proximity. The representations of the predicted functional nodes are enriched using attention mechanisms and subsequently fed into a Graph Multiset Transformer, which is trained with supervised contrastive (SupCon) and InfoNCE losses on perturbed protein structures. Our model demonstrates significant improvements in predicting Gene Ontology (GO) terms, effectively localizing functional residues within protein structures. The proposed framework provides a robust, scalable solution for protein function annotation, advancing the understanding of protein structure-function relationships in computational biology.

Recent years have witnessed a surge in the development of protein foundation models, significantly improving performance in protein prediction and generative tasks ranging from 3D structure prediction and protein design to conformational dynamics. However, the capabilities and limitations associated with these models remain poorly understood due to the absence of a unified evaluation framework. To fill this gap, we introduce ProteinBench, a holistic evaluation framework designed to enhance the transparency of protein foundation models. Our approach consists of three key components: (i) A taxonomic classification of tasks that broadly encompass the main challenges in the protein domain, based on the relationships between different protein modalities; (ii) A multi-metric evaluation approach that assesses performance across four key dimensions: quality, novelty, diversity, and robustness; and (iii) In-depth analyses from various user objectives, providing a holistic view of model performance. Our comprehensive evaluation of protein foundation models reveals several key findings that shed light on their current capabilities and limitations. To promote transparency and facilitate further research, we release the evaluation dataset, code, and a public leaderboard publicly for further analysis and a general modular toolkit. We intend for ProteinBench to be a living benchmark for establishing a standardized, in-depth evaluation framework for protein foundation models, driving their development and application while fostering collaboration within the field.

With the development of large language models, their ability to follow simple instructions has significantly improved. However, adhering to complex instructions remains a major challenge. Current approaches to generating complex instructions are often irrelevant to the current instruction requirements or suffer from limited scalability and diversity. Moreover, methods such as back-translation, while effective for simple instruction generation, fail to leverage the rich contents and structures in large web corpora. In this paper, we propose a novel automatic iterative refinement framework to generate complex instructions with constraints, which not only better reflects the requirements of real scenarios but also significantly enhances LLMs' ability to follow complex instructions. The AIR framework consists of two stages: (1)Generate an initial instruction from a document; (2)Iteratively refine instructions with LLM-as-judge guidance by comparing the model's output with the document to incorporate valuable constraints. Finally, we construct the AIR-10K dataset with 10K complex instructions and demonstrate that instructions generated with our approach significantly improve the model's ability to follow complex instructions, outperforming existing methods for instruction generation.

Proteins are dynamic molecular machines whose biological functions, spanning enzymatic catalysis, signal transduction, and structural adaptation, are intrinsically linked to their motions. Designing proteins with targeted dynamic properties, however, remains a challenge due to the complex, degenerate relationships between sequence, structure, and molecular motion. Here, we introduce VibeGen, a generative AI framework that enables end-to-end de novo protein design conditioned on normal mode vibrations. VibeGen employs an agentic dual-model architecture, comprising a protein designer that generates sequence candidates based on specified vibrational modes and a protein predictor that evaluates their dynamic accuracy. This approach synergizes diversity, accuracy, and novelty during the design process. Via full-atom molecular simulations as direct validation, we demonstrate that the designed proteins accurately reproduce the prescribed normal mode amplitudes across the backbone while adopting various stable, functionally relevant structures. Notably, generated sequences are de novo, exhibiting no significant similarity to natural proteins, thereby expanding the accessible protein space beyond evolutionary constraints. Our work integrates protein dynamics into generative protein design, and establishes a direct, bidirectional link between sequence and vibrational behavior, unlocking new pathways for engineering biomolecules with tailored dynamical and functional properties. This framework holds broad implications for the rational design of flexible enzymes, dynamic scaffolds, and biomaterials, paving the way toward dynamics-informed AI-driven protein engineering.

While large language models (LLMs) have exhibited impressive instruction-following capabilities, it is still unclear whether and to what extent they can respond to explicit constraints that might be entailed in various instructions. As a significant aspect of LLM alignment, it is thus important to formulate such a specialized set of instructions as well as investigate the resulting behavior of LLMs. To address this vacancy, we propose a new benchmark CoDI-Eval to systematically and comprehensively evaluate LLMs' responses to instructions with various constraints. We construct a large collection of constraints-attributed instructions as a test suite focused on both generalization and coverage. Specifically, we advocate an instruction diversification process to synthesize diverse forms of constraint expression and also deliberate the candidate task taxonomy with even finer-grained sub-categories. Finally, we automate the entire evaluation process to facilitate further developments. Different from existing studies on controllable text generation, CoDI-Eval extends the scope to the prevalent instruction-following paradigm for the first time. We provide extensive evaluations of representative LLMs (e.g., ChatGPT, Vicuna) on CoDI-Eval, revealing their limitations in following instructions with specific constraints and there is still a significant gap between open-source and commercial closed-source LLMs. We believe this benchmark will facilitate research into improving the controllability of LLMs' responses to instructions. Our data and code are available at https://github.com/Xt-cyh/CoDI-Eval.

Computational design of protein-binding proteins is a fundamental capability with broad utility in biomedical research and biotechnology. Recent methods have made strides against some target proteins, but on-demand creation of high-affinity binders without multiple rounds of experimental testing remains an unsolved challenge. This technical report introduces AlphaProteo, a family of machine learning models for protein design, and details its performance on the de novo binder design problem. With AlphaProteo, we achieve 3- to 300-fold better binding affinities and higher experimental success rates than the best existing methods on seven target proteins. Our results suggest that AlphaProteo can generate binders "ready-to-use" for many research applications using only one round of medium-throughput screening and no further optimization.

As opposed to scaling-up protein language models (PLMs), we seek improving performance via protein-specific optimization. Although the proportionality between the language model size and the richness of its learned representations is validated, we prioritize accessibility and pursue a path of data-efficient, cost-reduced, and knowledge-guided optimization. Through over twenty experiments ranging from masking, architecture, and pre-training data, we derive insights from protein-specific experimentation into building a model that interprets the language of life, optimally. We present Ankh, the first general-purpose PLM trained on Google's TPU-v4 surpassing the state-of-the-art performance with fewer parameters (<10% for pre-training, <7% for inference, and <30% for the embedding dimension). We provide a representative range of structure and function benchmarks where Ankh excels. We further provide a protein variant generation analysis on High-N and One-N input data scales where Ankh succeeds in learning protein evolutionary conservation-mutation trends and introducing functional diversity while retaining key structural-functional characteristics. We dedicate our work to promoting accessibility to research innovation via attainable resources.

In the field of antibody engineering, an essential task is to design a novel antibody whose paratopes bind to a specific antigen with correct epitopes. Understanding antibody structure and its paratope can facilitate a mechanistic understanding of its function. Therefore, antibody structure prediction from its sequence alone has always been a highly valuable problem for de novo antibody design. AlphaFold2, a breakthrough in the field of structural biology, provides a solution to predict protein structure based on protein sequences and computationally expensive coevolutionary multiple sequence alignments (MSAs). However, the computational efficiency and undesirable prediction accuracy of antibodies, especially on the complementarity-determining regions (CDRs) of antibodies limit their applications in the industrially high-throughput drug design. To learn an informative representation of antibodies, we employed a deep antibody language model (ALM) on curated sequences from the observed antibody space database via a transformer model. We also developed a novel model named xTrimoABFold to predict antibody structure from antibody sequence based on the pretrained ALM as well as efficient evoformers and structural modules. The model was trained end-to-end on the antibody structures in PDB by minimizing the ensemble loss of domain-specific focal loss on CDR and the frame-aligned point loss. xTrimoABFold outperforms AlphaFold2 and other protein language model based SOTAs, e.g., OmegaFold, HelixFold-Single, and IgFold with a large significant margin (30+\% improvement on RMSD) while performing 151 times faster than AlphaFold2. To the best of our knowledge, xTrimoABFold achieved state-of-the-art antibody structure prediction. Its improvement in both accuracy and efficiency makes it a valuable tool for de novo antibody design and could make further improvements in immuno-theory.

Traditional cooking recipes follow a structure which can be modelled very well if the rules and semantics of the different sections of the recipe text are analyzed and represented accurately. We propose a structure that can accurately represent the recipe as well as a pipeline to infer the best representation of the recipe in this uniform structure. The Ingredients section in a recipe typically lists down the ingredients required and corresponding attributes such as quantity, temperature, and processing state. This can be modelled by defining these attributes and their values. The physical entities which make up a recipe can be broadly classified into utensils, ingredients and their combinations that are related by cooking techniques. The instruction section lists down a series of events in which a cooking technique or process is applied upon these utensils and ingredients. We model these relationships in the form of tuples. Thus, using a combination of these methods we model cooking recipe in the dataset RecipeDB to show the efficacy of our method. This mined information model can have several applications which include translating recipes between languages, determining similarity between recipes, generation of novel recipes and estimation of the nutritional profile of recipes. For the purpose of recognition of ingredient attributes, we train the Named Entity Relationship (NER) models and analyze the inferences with the help of K-Means clustering. Our model presented with an F1 score of 0.95 across all datasets. We use a similar NER tagging model for labelling cooking techniques (F1 score = 0.88) and utensils (F1 score = 0.90) within the instructions section. Finally, we determine the temporal sequence of relationships between ingredients, utensils and cooking techniques for modeling the instruction steps.

Target proteins that lack accessible binding pockets and conformational stability have posed increasing challenges for drug development. Induced proximity strategies, such as PROTACs and molecular glues, have thus gained attention as pharmacological alternatives, but still require small molecule docking at binding pockets for targeted protein degradation (TPD). The computational design of protein-based binders presents unique opportunities to access undruggable targets, but have often relied on stable 3D structures or predictions for effective binder generation. Recently, we have leveraged the expressive latent spaces of protein language models (pLMs) for the prioritization of peptide binders from sequence alone, which we have then fused to E3 ubiquitin ligase domains, creating a CRISPR-analogous TPD system for target proteins. However, our methods rely on training discriminator models for ranking heuristically or unconditionally-derived guide peptides for their target binding capability. In this work, we introduce PepMLM, a purely target sequence-conditioned de novo generator of linear peptide binders. By employing a novel masking strategy that uniquely positions cognate peptide sequences at the terminus of target protein sequences, PepMLM tasks the state-of-the-art ESM-2 pLM to fully reconstruct the binder region, achieving low perplexities matching or improving upon previously-validated peptide-protein sequence pairs. After successful in silico benchmarking with AlphaFold-Multimer, we experimentally verify PepMLM's efficacy via fusion of model-derived peptides to E3 ubiquitin ligase domains, demonstrating endogenous degradation of target substrates in cellular models. In total, PepMLM enables the generative design of candidate binders to any target protein, without the requirement of target structure, empowering downstream programmable proteome editing applications.

Large language models (LLMs) have demonstrated significant success in natural language processing (NLP) tasks and have shown promising results in other domains such as protein sequence generation. However, there remain salient differences between LLMs used for NLP, which effectively handle multiple tasks and are available in small sizes, and protein language models that are often specialized for specific tasks and only exist in larger sizes. In this work, we introduce two small protein language models, based on Llama-3-8B and Phi-3-mini, that are capable of both uncontrollable and controllable protein generation. For the uncontrollable generation task, our best model achieves an average pLDDT score of 69.75, demonstrating robust performance in generating viable protein structures. For the controllable generation task, in which the model generates proteins according to properties specified in the prompt, we achieve a remarkable average TM-Score of 0.84, indicating high structural similarity to target proteins. We chose 10 properties, including six classes of enzymes, to extend the capabilities of prior protein language models. Our approach utilizes the Low-Rank Adaptor (LoRA) technique, reducing trainable parameters to just 4% of the original model size, lowering computational requirements. By using a subset of the UniRef50 dataset and small models, we reduced the overall training time by 70% without compromising performance. Notably, Phi-3-mini reduced trainable parameters by 60%, decreasing training cost by 30% compared to Llama 3. Consequently, Phi-3 achieved a comparable TM-Score of 0.81, demonstrating that smaller models can match the performance of larger ones, like Llama 3. We also demonstrate the deployment of our models on the energy efficient ET-SoC-1 chip, significantly improving the TPS/W by a factor of 3.

The ability to accurately model the fitness landscape of protein sequences is critical to a wide range of applications, from quantifying the effects of human variants on disease likelihood, to predicting immune-escape mutations in viruses and designing novel biotherapeutic proteins. Deep generative models of protein sequences trained on multiple sequence alignments have been the most successful approaches so far to address these tasks. The performance of these methods is however contingent on the availability of sufficiently deep and diverse alignments for reliable training. Their potential scope is thus limited by the fact many protein families are hard, if not impossible, to align. Large language models trained on massive quantities of non-aligned protein sequences from diverse families address these problems and show potential to eventually bridge the performance gap. We introduce Tranception, a novel transformer architecture leveraging autoregressive predictions and retrieval of homologous sequences at inference to achieve state-of-the-art fitness prediction performance. Given its markedly higher performance on multiple mutants, robustness to shallow alignments and ability to score indels, our approach offers significant gain of scope over existing approaches. To enable more rigorous model testing across a broader range of protein families, we develop ProteinGym -- an extensive set of multiplexed assays of variant effects, substantially increasing both the number and diversity of assays compared to existing benchmarks.

While artificial intelligence has made remarkable strides in revealing the relationship between biological macromolecules' primary sequence and tertiary structure, designing RNA sequences based on specified tertiary structures remains challenging. Though existing approaches in protein design have thoroughly explored structure-to-sequence dependencies in proteins, RNA design still confronts difficulties due to structural complexity and data scarcity. Moreover, direct transplantation of protein design methodologies into RNA design fails to achieve satisfactory outcomes although sharing similar structural components. In this study, we aim to systematically construct a data-driven RNA design pipeline. We crafted a large, well-curated benchmark dataset and designed a comprehensive structural modeling approach to represent the complex RNA tertiary structure. More importantly, we proposed a hierarchical data-efficient representation learning framework that learns structural representations through contrastive learning at both cluster-level and sample-level to fully leverage the limited data. By constraining data representations within a limited hyperspherical space, the intrinsic relationships between data points could be explicitly imposed. Moreover, we incorporated extracted secondary structures with base pairs as prior knowledge to facilitate the RNA design process. Extensive experiments demonstrate the effectiveness of our proposed method, providing a reliable baseline for future RNA design tasks. The source code and benchmark dataset are available at https://github.com/A4Bio/RDesign.

Multiple sequence alignments (MSAs) of proteins encode rich biological information and have been workhorses in bioinformatic methods for tasks like protein design and protein structure prediction for decades. Recent breakthroughs like AlphaFold2 that use transformers to attend directly over large quantities of raw MSAs have reaffirmed their importance. Generation of MSAs is highly computationally intensive, however, and no datasets comparable to those used to train AlphaFold2 have been made available to the research community, hindering progress in machine learning for proteins. To remedy this problem, we introduce OpenProteinSet, an open-source corpus of more than 16 million MSAs, associated structural homologs from the Protein Data Bank, and AlphaFold2 protein structure predictions. We have previously demonstrated the utility of OpenProteinSet by successfully retraining AlphaFold2 on it. We expect OpenProteinSet to be broadly useful as training and validation data for 1) diverse tasks focused on protein structure, function, and design and 2) large-scale multimodal machine learning research.

Consistency and reliability are crucial for conducting AI research. Many famous research fields, such as object detection, have been compared and validated with solid benchmark frameworks. After AlphaFold2, the protein folding task has entered a new phase, and many methods are proposed based on the component of AlphaFold2. The importance of a unified research framework in protein folding contains implementations and benchmarks to consistently and fairly compare various approaches. To achieve this, we present Solvent, an protein folding framework that supports significant components of state-of-th-arts models in the manner of off-the-shelf interface Solvent contains different models implemented in a unified codebase and supports training and evaluation for defined models on the same dataset. We benchmark well-known algorithms and their components and provide experiments that give helpful insights into the protein structure modeling field. We hope that Solvent will increase the reliability and consistency of proposed models and gives efficiency in both speed and costs, resulting in acceleration on protein folding modeling research. The code is available at https://github.com/kakaobrain/solvent, and the project will continue to be developed.

Attention-based models trained on protein sequences have demonstrated incredible success at classification and generation tasks relevant for artificial intelligence-driven protein design. However, we lack a sufficient understanding of how very large-scale models and data play a role in effective protein model development. We introduce a suite of protein language models, named ProGen2, that are scaled up to 6.4B parameters and trained on different sequence datasets drawn from over a billion proteins from genomic, metagenomic, and immune repertoire databases. ProGen2 models show state-of-the-art performance in capturing the distribution of observed evolutionary sequences, generating novel viable sequences, and predicting protein fitness without additional finetuning. As large model sizes and raw numbers of protein sequences continue to become more widely accessible, our results suggest that a growing emphasis needs to be placed on the data distribution provided to a protein sequence model. We release the ProGen2 models and code at https://github.com/salesforce/progen.

Inverse protein folding -- the task of predicting a protein sequence from its backbone atom coordinates -- has surfaced as an important problem in the "top down", de novo design of proteins. Contemporary approaches have cast this problem as a conditional generative modelling problem, where a large generative model over protein sequences is conditioned on the backbone. While these generative models very rapidly produce promising sequences, independent draws from generative models may fail to produce sequences that reliably fold to the correct backbone. Furthermore, it is challenging to adapt pure generative approaches to other settings, e.g., when constraints exist. In this paper, we cast the problem of improving generated inverse folds as an optimization problem that we solve using recent advances in "deep" or "latent space" Bayesian optimization. Our approach consistently produces protein sequences with greatly reduced structural error to the target backbone structure as measured by TM score and RMSD while using fewer computational resources. Additionally, we demonstrate other advantages of an optimization-based approach to the problem, such as the ability to handle constraints.

Proteins power a vast array of functional processes in living cells. The capability to create new proteins with designed structures and functions would thus enable the engineering of cellular behavior and development of protein-based therapeutics and materials. Structure-based protein design aims to find structures that are designable (can be realized by a protein sequence), novel (have dissimilar geometry from natural proteins), and diverse (span a wide range of geometries). While advances in protein structure prediction have made it possible to predict structures of novel protein sequences, the combinatorially large space of sequences and structures limits the practicality of search-based methods. Generative models provide a compelling alternative, by implicitly learning the low-dimensional structure of complex data distributions. Here, we leverage recent advances in denoising diffusion probabilistic models and equivariant neural networks to develop Genie, a generative model of protein structures that performs discrete-time diffusion using a cloud of oriented reference frames in 3D space. Through in silico evaluations, we demonstrate that Genie generates protein backbones that are more designable, novel, and diverse than existing models. This indicates that Genie is capturing key aspects of the distribution of protein structure space and facilitates protein design with high success rates. Code for generating new proteins and training new versions of Genie is available at https://github.com/aqlaboratory/genie.

Cryo-electron microscopy (cryo-EM) is a technique for reconstructing the 3-dimensional (3D) structure of biomolecules (especially large protein complexes and molecular assemblies). As the resolution increases to the near-atomic scale, building protein structures de novo from cryo-EM maps becomes possible. Recently, recognition-based de novo building methods have shown the potential to streamline this process. However, it cannot build a complete structure due to the low signal-to-noise ratio (SNR) problem. At the same time, AlphaFold has led to a great breakthrough in predicting protein structures. This has inspired us to combine fragment recognition and structure prediction methods to build a complete structure. In this paper, we propose a new method named FFF that bridges protein structure prediction and protein structure recognition with flexible fitting. First, a multi-level recognition network is used to capture various structural features from the input 3D cryo-EM map. Next, protein structural fragments are generated using pseudo peptide vectors and a protein sequence alignment method based on these extracted features. Finally, a complete structural model is constructed using the predicted protein fragments via flexible fitting. Based on our benchmark tests, FFF outperforms the baseline methods for building complete protein structures.

Drug discovery typically consists of multiple steps, including identifying a target protein key to a disease's etiology, validating that interacting with this target could prevent symptoms or cure the disease, discovering a small molecule or biologic therapeutic to interact with it, and optimizing the candidate molecule through a complex landscape of required properties. Drug discovery related tasks often involve prediction and generation while considering multiple entities that potentially interact, which poses a challenge for typical AI models. For this purpose we present MAMMAL - Molecular Aligned Multi-Modal Architecture and Language - a method that we applied to create a versatile multi-task foundation model ibm/biomed.omics.bl.sm.ma-ted-458m that learns from large-scale biological datasets (2 billion samples) across diverse modalities, including proteins, small molecules, and genes. We introduce a prompt syntax that supports a wide range of classification, regression, and generation tasks. It allows combining different modalities and entity types as inputs and/or outputs. Our model handles combinations of tokens and scalars and enables the generation of small molecules and proteins, property prediction, and transcriptomic lab test predictions. We evaluated the model on 11 diverse downstream tasks spanning different steps within a typical drug discovery pipeline, where it reaches new SOTA in 9 tasks and is comparable to SOTA in 2 tasks. This performance is achieved while using a unified architecture serving all tasks, in contrast to the original SOTA performance achieved using tailored architectures. The model code and pretrained weights are publicly available at https://github.com/BiomedSciAI/biomed-multi-alignment and https://huggingface.co/ibm/biomed.omics.bl.sm.ma-ted-458m.

Aligned instruction following models can better fulfill user requests than their unaligned counterparts. However, it has been shown that there is a length bias in evaluation of such models, and that training algorithms tend to exploit this bias by learning longer responses. In this work we show how to train models that can be controlled at inference time with instructions containing desired length constraints. Such models are superior in length instructed evaluations, outperforming standard instruction following models such as GPT4, Llama 3 and Mixtral.

To enhance the performance of large language models (LLMs) in biomedical natural language processing (BioNLP) by introducing a domain-specific instruction dataset and examining its impact when combined with multi-task learning principles. We created the BioInstruct, comprising 25,005 instructions to instruction-tune LLMs(LLaMA 1 & 2, 7B & 13B version). The instructions were created by prompting the GPT-4 language model with three-seed samples randomly drawn from an 80 human curated instructions. We employed Low-Rank Adaptation(LoRA) for parameter-efficient fine-tuning. We then evaluated these instruction-tuned LLMs on several BioNLP tasks, which can be grouped into three major categories: question answering(QA), information extraction(IE), and text generation(GEN). We also examined whether categories(e.g., QA, IE, and generation) of instructions impact model performance. Comparing with LLMs without instruction-tuned, our instruction-tuned LLMs demonstrated marked performance gains: 17.3% in QA, 5.7% in IE, and 96% in Generation tasks. Our 7B-parameter instruction-tuned LLaMA 1 model was competitive or even surpassed other LLMs in the biomedical domain that were also fine-tuned from LLaMA 1 with vast domain-specific data or a variety of tasks. Our results also show that the performance gain is significantly higher when instruction fine-tuning is conducted with closely related tasks. Our findings align with the observations of multi-task learning, suggesting the synergies between two tasks. The BioInstruct dataset serves as a valuable resource and instruction tuned LLMs lead to the best performing BioNLP applications.

The computational prediction and design of peptide binders targeting specific linear epitopes is crucial in biological and biomedical research, yet it remains challenging due to their highly dynamic nature and the scarcity of experimentally solved binding data. To address this problem, we built an unprecedentedly large-scale library of peptide pairs within stable secondary structures (beta sheets), leveraging newly available AlphaFold predicted structures. We then developed a machine learning method based on the Transformer architecture for the design of specific linear binders, in analogy to a language translation task. Our method, TransformerBeta, accurately predicts specific beta strand interactions and samples sequences with beta sheet-like molecular properties, while capturing interpretable physico-chemical interaction patterns. As such, it can propose specific candidate binders targeting linear epitope for experimental validation to inform protein design.

Protein design, a grand challenge of the day, involves optimization on a fitness landscape, and leading methods adopt a model-based approach where a model is trained on a training set (protein sequences and fitness) and proposes candidates to explore next. These methods are challenged by sparsity of high-fitness samples in the training set, a problem that has been in the literature. A less recognized but equally important problem stems from the distribution of training samples in the design space: leading methods are not designed for scenarios where the desired optimum is in a region that is not only poorly represented in training data, but also relatively far from the highly represented low-fitness regions. We show that this problem of "separation" in the design space is a significant bottleneck in existing model-based optimization tools and propose a new approach that uses a novel VAE as its search model to overcome the problem. We demonstrate its advantage over prior methods in robustly finding improved samples, regardless of the imbalance and separation between low- and high-fitness training samples. Our comprehensive benchmark on real and semi-synthetic protein datasets as well as solution design for physics-informed neural networks, showcases the generality of our approach in discrete and continuous design spaces. Our implementation is available at https://github.com/sabagh1994/PGVAE.

Predicting which proteins interact together from amino-acid sequences is an important task. We develop a method to pair interacting protein sequences which leverages the power of protein language models trained on multiple sequence alignments, such as MSA Transformer and the EvoFormer module of AlphaFold. We formulate the problem of pairing interacting partners among the paralogs of two protein families in a differentiable way. We introduce a method called DiffPALM that solves it by exploiting the ability of MSA Transformer to fill in masked amino acids in multiple sequence alignments using the surrounding context. MSA Transformer encodes coevolution between functionally or structurally coupled amino acids. We show that it captures inter-chain coevolution, while it was trained on single-chain data, which means that it can be used out-of-distribution. Relying on MSA Transformer without fine-tuning, DiffPALM outperforms existing coevolution-based pairing methods on difficult benchmarks of shallow multiple sequence alignments extracted from ubiquitous prokaryotic protein datasets. It also outperforms an alternative method based on a state-of-the-art protein language model trained on single sequences. Paired alignments of interacting protein sequences are a crucial ingredient of supervised deep learning methods to predict the three-dimensional structure of protein complexes. DiffPALM substantially improves the structure prediction of some eukaryotic protein complexes by AlphaFold-Multimer, without significantly deteriorating any of those we tested. It also achieves competitive performance with using orthology-based pairing.

Instruction tuning, a new learning paradigm that fine-tunes pre-trained language models on tasks specified through instructions, has shown promising zero-shot performance on various natural language processing tasks. However, it has yet to be explored for vision and multimodal tasks. In this work, we introduce MUL-TIINSTRUCT, the first multimodal instruction tuning benchmark dataset that consists of 62 diverse multimodal tasks in a unified seq-to-seq format covering 10 broad categories. The tasks are derived from 21 existing open-source datasets and each task is equipped with 5 expert-written instructions. We take OFA as the base pre-trained model for multimodal instruction tuning, and to further improve its zero-shot performance, we explore multiple transfer learning strategies to leverage the large-scale NATURAL INSTRUCTIONS dataset. Experimental results demonstrate strong zero-shot performance on various unseen multimodal tasks and the benefit of transfer learning from a text-only instruction dataset. We also design a new evaluation metric - Sensitivity, to evaluate how sensitive the model is to the variety of instructions. Our results indicate that fine-tuning the model on a diverse set of tasks and instructions leads to a reduced sensitivity to variations in instructions for each task.

When manipulating three-dimensional data, it is possible to ensure that rotational and translational symmetries are respected by applying so-called SE(3)-equivariant models. Protein structure prediction is a prominent example of a task which displays these symmetries. Recent work in this area has successfully made use of an SE(3)-equivariant model, applying an iterative SE(3)-equivariant attention mechanism. Motivated by this application, we implement an iterative version of the SE(3)-Transformer, an SE(3)-equivariant attention-based model for graph data. We address the additional complications which arise when applying the SE(3)-Transformer in an iterative fashion, compare the iterative and single-pass versions on a toy problem, and consider why an iterative model may be beneficial in some problem settings. We make the code for our implementation available to the community.

Task semantics can be expressed by a set of input-to-output examples or a piece of textual instruction. Conventional machine learning approaches for natural language processing (NLP) mainly rely on the availability of large-scale sets of task-specific examples. Two issues arise: first, collecting task-specific labeled examples does not apply to scenarios where tasks may be too complicated or costly to annotate, or the system is required to handle a new task immediately; second, this is not user-friendly since end-users are probably more willing to provide task description rather than a set of examples before using the system. Therefore, the community is paying increasing interest in a new supervision-seeking paradigm for NLP: learning from task instructions. Despite its impressive progress, there are some common issues that the community struggles with. This survey paper tries to summarize and provide insights into the current research on instruction learning, particularly by answering the following questions: (i) What is task instruction, and what instruction types exist? (ii) How to model instructions? (iii) What factors influence and explain the instructions' performance? (iv) What challenges remain in instruction learning? To our knowledge, this is the first comprehensive survey about textual instructions.

Quantum computing has gained a lot of attention recently, and scientists have seen potential applications in this field using quantum computing for Cryptography and Communication to Machine Learning and Healthcare. Protein folding has been one of the most interesting areas to study, and it is also one of the biggest problems of biochemistry. Each protein folds distinctively, and the difficulty of finding its stable shape rapidly increases with an increase in the number of amino acids in the chain. A moderate protein has about 100 amino acids, and the number of combinations one needs to verify to find the stable structure is enormous. At some point, the number of these combinations will be so vast that classical computers cannot even attempt to solve them. In this paper, we examine how this problem can be solved with the help of quantum computing using two different algorithms, Variational Quantum Eigensolver (VQE) and Quantum Approximate Optimization Algorithm (QAOA), using Qiskit Nature. We compare the results of different quantum hardware and simulators and check how error mitigation affects the performance. Further, we make comparisons with SoTA algorithms and evaluate the reliability of the method.

Recent research trends in computational biology have increasingly focused on integrating text and bio-entity modeling, especially in the context of molecules and proteins. However, previous efforts like BioT5 faced challenges in generalizing across diverse tasks and lacked a nuanced understanding of molecular structures, particularly in their textual representations (e.g., IUPAC). This paper introduces BioT5+, an extension of the BioT5 framework, tailored to enhance biological research and drug discovery. BioT5+ incorporates several novel features: integration of IUPAC names for molecular understanding, inclusion of extensive bio-text and molecule data from sources like bioRxiv and PubChem, the multi-task instruction tuning for generality across tasks, and a novel numerical tokenization technique for improved processing of numerical data. These enhancements allow BioT5+ to bridge the gap between molecular representations and their textual descriptions, providing a more holistic understanding of biological entities, and largely improving the grounded reasoning of bio-text and bio-sequences. The model is pre-trained and fine-tuned with a large number of experiments, including 3 types of problems (classification, regression, generation), 15 kinds of tasks, and 21 total benchmark datasets, demonstrating the remarkable performance and state-of-the-art results in most cases. BioT5+ stands out for its ability to capture intricate relationships in biological data, thereby contributing significantly to bioinformatics and computational biology. Our code is available at https://github.com/QizhiPei/BioT5.

Designing de novo proteins beyond those found in nature holds significant promise for advancements in both scientific and engineering applications. Current methodologies for protein design often rely on AI-based models, such as surrogate models that address end-to-end problems by linking protein structure to material properties or vice versa. However, these models frequently focus on specific material objectives or structural properties, limiting their flexibility when incorporating out-of-domain knowledge into the design process or comprehensive data analysis is required. In this study, we introduce ProtAgents, a platform for de novo protein design based on Large Language Models (LLMs), where multiple AI agents with distinct capabilities collaboratively address complex tasks within a dynamic environment. The versatility in agent development allows for expertise in diverse domains, including knowledge retrieval, protein structure analysis, physics-based simulations, and results analysis. The dynamic collaboration between agents, empowered by LLMs, provides a versatile approach to tackling protein design and analysis problems, as demonstrated through diverse examples in this study. The problems of interest encompass designing new proteins, analyzing protein structures and obtaining new first-principles data -- natural vibrational frequencies -- via physics simulations. The concerted effort of the system allows for powerful automated and synergistic design of de novo proteins with targeted mechanical properties. The flexibility in designing the agents, on one hand, and their capacity in autonomous collaboration through the dynamic LLM-based multi-agent environment on the other hand, unleashes great potentials of LLMs in addressing multi-objective materials problems and opens up new avenues for autonomous materials discovery and design.

Antibodies comprise the most versatile class of binding molecules, with numerous applications in biomedicine. Computational design of antibodies involves generating novel and diverse sequences, while maintaining structural consistency. Unique to antibodies, designing the complementarity-determining region (CDR), which determines the antigen binding affinity and specificity, creates its own unique challenges. Recent deep learning models have shown impressive results, however the limited number of known antibody sequence/structure pairs frequently leads to degraded performance, particularly lacking diversity in the generated sequences. In our work we address this challenge by leveraging Model Reprogramming (MR), which repurposes pretrained models on a source language to adapt to the tasks that are in a different language and have scarce data - where it may be difficult to train a high-performing model from scratch or effectively fine-tune an existing pre-trained model on the specific task. Specifically, we introduce ReprogBert in which a pretrained English language model is repurposed for protein sequence infilling - thus considers cross-language adaptation using less data. Results on antibody design benchmarks show that our model on low-resourced antibody sequence dataset provides highly diverse CDR sequences, up to more than a two-fold increase of diversity over the baselines, without losing structural integrity and naturalness. The generated sequences also demonstrate enhanced antigen binding specificity and virus neutralization ability. Code is available at https://github.com/IBM/ReprogBERT

Building a general-purpose task model similar to ChatGPT has been an important research direction for gene large language models. Instruction fine-tuning is a key component in building ChatGPT, but existing instructions are primarily based on natural language. Natural language and gene sequences have significant differences in tokenization and encoding. Therefore, constructing a multilingual model that can handle both natural language and gene sequences is crucial for solving this problem.In this paper, we expand the capabilities of the LLaMA large language model to include gene language. This involves expanding the vocabulary using the Byte Pair Encoding (BPE) method, specifically tailored for DNA and protein sequences, and conducting further pre-training on these sequences. We then convert various downstream gene task data into a unified format for instruction fine-tuning and further fine-tune the model on this data.Our study demonstrates that a mixed model of gene and natural language, fine-tuned with instructions, achieves results comparable to the current state-of-the-art (SOTA) in tasks such as gene classification and gene sequence interaction. This provides a promising direction for building a unified large language model for gene tasks.

We are now witnessing significant progress of deep learning methods in a variety of tasks (or datasets) of proteins. However, there is a lack of a standard benchmark to evaluate the performance of different methods, which hinders the progress of deep learning in this field. In this paper, we propose such a benchmark called PEER, a comprehensive and multi-task benchmark for Protein sEquence undERstanding. PEER provides a set of diverse protein understanding tasks including protein function prediction, protein localization prediction, protein structure prediction, protein-protein interaction prediction, and protein-ligand interaction prediction. We evaluate different types of sequence-based methods for each task including traditional feature engineering approaches, different sequence encoding methods as well as large-scale pre-trained protein language models. In addition, we also investigate the performance of these methods under the multi-task learning setting. Experimental results show that large-scale pre-trained protein language models achieve the best performance for most individual tasks, and jointly training multiple tasks further boosts the performance. The datasets and source codes of this benchmark are all available at https://github.com/DeepGraphLearning/PEER_Benchmark

Instruction tuning has emerged as the key in aligning large language models (LLMs) with specific task instructions, thereby mitigating the discrepancy between the next-token prediction objective and users' actual goals. To reduce the labor and time cost to collect or annotate data by humans, researchers start to explore the use of LLMs to generate instruction-aligned synthetic data. Recent works focus on generating diverse instructions and applying LLM to increase instruction complexity, often neglecting downstream use cases. It remains unclear how to tailor high-quality data to elicit better instruction-following abilities in different target instruction distributions and LLMs. To this end, we introduce CodecLM, a general framework for adaptively generating high-quality synthetic data for LLM alignment with different downstream instruction distributions and LLMs. Drawing on the Encode-Decode principles, we use LLMs as codecs to guide the data generation process. We first encode seed instructions into metadata, which are concise keywords generated on-the-fly to capture the target instruction distribution, and then decode metadata to create tailored instructions. We also introduce Self-Rubrics and Contrastive Filtering during decoding to tailor data-efficient samples. Extensive experiments on four open-domain instruction following benchmarks validate the effectiveness of CodecLM over the current state-of-the-arts.

Large Language Models (LLMs) have demonstrated remarkable generalization and instruction-following capabilities with instruction tuning. The advancements in LLMs and instruction tuning have led to the development of Large Vision-Language Models (LVLMs). However, the competency of the LLMs and instruction tuning have been less explored in the molecular domain. Thus, we propose LLaMo: Large Language Model-based Molecular graph assistant, which is an end-to-end trained large molecular graph-language model. To bridge the discrepancy between the language and graph modalities, we present the multi-level graph projector that transforms graph representations into graph tokens by abstracting the output representations of each GNN layer and motif representations with the cross-attention mechanism. We also introduce machine-generated molecular graph instruction data to instruction-tune the large molecular graph-language model for general-purpose molecule and language understanding. Our extensive experiments demonstrate that LLaMo shows the best performance on diverse tasks, such as molecular description generation, property prediction, and IUPAC name prediction. The code of LLaMo is available at https://github.com/mlvlab/LLaMo.

Large-scale Protein Language Models (PLMs) have improved performance in protein prediction tasks, ranging from 3D structure prediction to various function predictions. In particular, AlphaFold, a ground-breaking AI system, could potentially reshape structural biology. However, the utility of the PLM module in AlphaFold, Evoformer, has not been explored beyond structure prediction. In this paper, we investigate the representation ability of three popular PLMs: ESM-1b (single sequence), MSA-Transformer (multiple sequence alignment) and Evoformer (structural), with a special focus on Evoformer. Specifically, we aim to answer the following key questions: (i) Does the Evoformer trained as part of AlphaFold produce representations amenable to predicting protein function? (ii) If yes, can Evoformer replace ESM-1b and MSA-Transformer? (ii) How much do these PLMs rely on evolution-related protein data? In this regard, are they complementary to each other? We compare these models by empirical study along with new insights and conclusions. All code and datasets for reproducibility are available at https://github.com/elttaes/Revisiting-PLMs.

Following natural instructions is crucial for the effective application of Retrieval-Augmented Generation (RAG) systems. Despite recent advancements in Large Language Models (LLMs), research on assessing and improving instruction-following (IF) alignment within the RAG domain remains limited. To address this issue, we propose VIF-RAG, the first automated, scalable, and verifiable synthetic pipeline for instruction-following alignment in RAG systems. We start by manually crafting a minimal set of atomic instructions (<100) and developing combination rules to synthesize and verify complex instructions for a seed set. We then use supervised models for instruction rewriting while simultaneously generating code to automate the verification of instruction quality via a Python executor. Finally, we integrate these instructions with extensive RAG and general data samples, scaling up to a high-quality VIF-RAG-QA dataset (>100k) through automated processes. To further bridge the gap in instruction-following auto-evaluation for RAG systems, we introduce FollowRAG Benchmark, which includes approximately 3K test samples, covering 22 categories of general instruction constraints and four knowledge-intensive QA datasets. Due to its robust pipeline design, FollowRAG can seamlessly integrate with different RAG benchmarks. Using FollowRAG and eight widely-used IF and foundational abilities benchmarks for LLMs, we demonstrate that VIF-RAG markedly enhances LLM performance across a broad range of general instruction constraints while effectively leveraging its capabilities in RAG scenarios. Further analysis offers practical insights for achieving IF alignment in RAG systems. Our code and datasets are released at https://FollowRAG.github.io.

In recent years, instruction tuning has gained increasing attention and emerged as a crucial technique to enhance the capabilities of Large Language Models (LLMs). To construct high-quality instruction datasets, many instruction processing approaches have been proposed, aiming to achieve a delicate balance between data quantity and data quality. Nevertheless, due to inconsistencies that persist among various instruction processing methods, there is no standard open-source instruction processing implementation framework available for the community, which hinders practitioners from further developing and advancing. To facilitate instruction processing research and development, we present EasyInstruct, an easy-to-use instruction processing framework for LLMs, which modularizes instruction generation, selection, and prompting, while also considering their combination and interaction. EasyInstruct is publicly released and actively maintained at https://github.com/zjunlp/EasyInstruct, along with a running demo App at https://huggingface.co/spaces/zjunlp/EasyInstruct for quick-start, calling for broader research centered on instruction data.

By conditioning on natural language instructions, large language models (LLMs) have displayed impressive capabilities as general-purpose computers. However, task performance depends significantly on the quality of the prompt used to steer the model, and most effective prompts have been handcrafted by humans. Inspired by classical program synthesis and the human approach to prompt engineering, we propose Automatic Prompt Engineer (APE) for automatic instruction generation and selection. In our method, we treat the instruction as the "program," optimized by searching over a pool of instruction candidates proposed by an LLM in order to maximize a chosen score function. To evaluate the quality of the selected instruction, we evaluate the zero-shot performance of another LLM following the selected instruction. Experiments on 24 NLP tasks show that our automatically generated instructions outperform the prior LLM baseline by a large margin and achieve better or comparable performance to the instructions generated by human annotators on 19/24 tasks. We conduct extensive qualitative and quantitative analyses to explore the performance of APE. We show that APE-engineered prompts can be applied to steer models toward truthfulness and/or informativeness, as well as to improve few-shot learning performance by simply prepending them to standard in-context learning prompts. Please check out our webpage at https://sites.google.com/view/automatic-prompt-engineer.

The integration of molecule and language has garnered increasing attention in molecular science. Recent advancements in Language Models (LMs) have demonstrated potential for the comprehensive modeling of molecule and language. However, existing works exhibit notable limitations. Most existing works overlook the modeling of 3D information, which is crucial for understanding molecular structures and also functions. While some attempts have been made to leverage external structure encoding modules to inject the 3D molecular information into LMs, there exist obvious difficulties that hinder the integration of molecular structure and language text, such as modality alignment and separate tuning. To bridge this gap, we propose 3D-MolT5, a unified framework designed to model both 1D molecular sequence and 3D molecular structure. The key innovation lies in our methodology for mapping fine-grained 3D substructure representations (based on 3D molecular fingerprints) to a specialized 3D token vocabulary for 3D-MolT5. This 3D structure token vocabulary enables the seamless combination of 1D sequence and 3D structure representations in a tokenized format, allowing 3D-MolT5 to encode molecular sequence (SELFIES), molecular structure, and text sequences within a unified architecture. Alongside, we further introduce 1D and 3D joint pre-training to enhance the model's comprehension of these diverse modalities in a joint representation space and better generalize to various tasks for our foundation model. Through instruction tuning on multiple downstream datasets, our proposed 3D-MolT5 shows superior performance than existing methods in molecular property prediction, molecule captioning, and text-based molecule generation tasks. Our code will be available on GitHub soon.

Instruction-following made modern large language models (LLMs) helpful assistants. However, the key to taming LLMs on complex instructions remains mysterious, for that there are huge gaps between models trained by open-source community and those trained by leading companies. To bridge the gap, we propose a simple and scalable approach UltraIF for building LLMs that can follow complex instructions with open-source data. UltraIF first decomposes real-world user prompts into simpler queries, constraints, and corresponding evaluation questions for the constraints. Then, we train an UltraComposer to compose constraint-associated prompts with evaluation questions. This prompt composer allows us to synthesize complicated instructions as well as filter responses with evaluation questions. In our experiment, for the first time, we successfully align LLaMA-3.1-8B-Base to catch up with its instruct version on 5 instruction-following benchmarks without any benchmark information, using only 8B model as response generator and evaluator. The aligned model also achieved competitive scores on other benchmarks. Moreover, we also show that UltraIF could further improve LLaMA-3.1-8B-Instruct through self-alignment, motivating broader use cases for the method. Our code will be available at https://github.com/kkk-an/UltraIF.

Large Language Models (LLMs), particularly those similar to ChatGPT, have significantly influenced the field of Natural Language Processing (NLP). While these models excel in general language tasks, their performance in domain-specific downstream tasks such as biomedical and clinical Named Entity Recognition (NER), Relation Extraction (RE), and Medical Natural Language Inference (NLI) is still evolving. In this context, our study investigates the potential of instruction tuning for biomedical language processing, applying this technique to two general LLMs of substantial scale. We present a comprehensive, instruction-based model trained on a dataset that consists of approximately 200,000 instruction-focused samples. This dataset represents a carefully curated compilation of existing data, meticulously adapted and reformatted to align with the specific requirements of our instruction-based tasks. This initiative represents an important step in utilising such models to achieve results on par with specialised encoder-only models like BioBERT and BioClinicalBERT for various classical biomedical NLP tasks. Our work includes an analysis of the dataset's composition and its impact on model performance, providing insights into the intricacies of instruction tuning. By sharing our codes, models, and the distinctively assembled instruction-based dataset, we seek to encourage ongoing research and development in this area.

Existing visual instruction tuning methods typically prompt large language models with textual descriptions to generate instruction-following data. Despite the promising performance achieved, these descriptions are derived from image annotations, which are oftentimes coarse-grained. Furthermore, the instructions might even contradict the visual content without observing the entire visual context. To address this challenge, we introduce a fine-grained visual instruction dataset, LVIS-Instruct4V, which contains 220K visually aligned and context-aware instructions produced by prompting the powerful GPT-4V with images from LVIS. Through experimental validation and case studies, we demonstrate that high-quality visual instructional data could improve the performance of LLaVA-1.5, a state-of-the-art large multimodal model, across a wide spectrum of benchmarks by clear margins. Notably, by simply replacing the LLaVA-Instruct with our LVIS-Instruct4V, we achieve better results than LLaVA on most challenging LMM benchmarks, e.g., LLaVA^w (76.7 vs. 70.7) and MM-Vet (40.2 vs. 35.4). We release our data and model at https://github.com/X2FD/LVIS-INSTRUCT4V.

Multistep instructions, such as recipes and how-to guides, greatly benefit from visual aids, such as a series of images that accompany the instruction steps. While Large Language Models (LLMs) have become adept at generating coherent textual steps, Large Vision/Language Models (LVLMs) are less capable of generating accompanying image sequences. The most challenging aspect is that each generated image needs to adhere to the relevant textual step instruction, as well as be visually consistent with earlier images in the sequence. To address this problem, we propose an approach for generating consistent image sequences, which integrates a Latent Diffusion Model (LDM) with an LLM to transform the sequence into a caption to maintain the semantic coherence of the sequence. In addition, to maintain the visual coherence of the image sequence, we introduce a copy mechanism to initialise reverse diffusion processes with a latent vector iteration from a previously generated image from a relevant step. Both strategies will condition the reverse diffusion process on the sequence of instruction steps and tie the contents of the current image to previous instruction steps and corresponding images. Experiments show that the proposed approach is preferred by humans in 46.6% of the cases against 26.6% for the second best method. In addition, automatic metrics showed that the proposed method maintains semantic coherence and visual consistency across steps in both domains.

We describe the accurate prediction of ligand-protein interaction (LPI) affinities, also known as drug-target interactions (DTI), with instruction fine-tuned pretrained generative small language models (SLMs). We achieved accurate predictions for a range of affinity values associated with ligand-protein interactions on out-of-sample data in a zero-shot setting. Only the SMILES string of the ligand and the amino acid sequence of the protein were used as the model inputs. Our results demonstrate a clear improvement over machine learning (ML) and free-energy perturbation (FEP+) based methods in accurately predicting a range of ligand-protein interaction affinities, which can be leveraged to further accelerate drug discovery campaigns against challenging therapeutic targets.

Through evolution, nature has presented a set of remarkable protein materials, including elastins, silks, keratins and collagens with superior mechanical performances that play crucial roles in mechanobiology. However, going beyond natural designs to discover proteins that meet specified mechanical properties remains challenging. Here we report a generative model that predicts protein designs to meet complex nonlinear mechanical property-design objectives. Our model leverages deep knowledge on protein sequences from a pre-trained protein language model and maps mechanical unfolding responses to create novel proteins. Via full-atom molecular simulations for direct validation, we demonstrate that the designed proteins are novel, and fulfill the targeted mechanical properties, including unfolding energy and mechanical strength, as well as the detailed unfolding force-separation curves. Our model offers rapid pathways to explore the enormous mechanobiological protein sequence space unconstrained by biological synthesis, using mechanical features as target to enable the discovery of protein materials with superior mechanical properties.

Understanding molecules is key to understanding organisms and driving advances in drug discovery, requiring interdisciplinary knowledge across chemistry and biology. Although large molecular language models have achieved notable success in interpreting molecular structures, their instruction datasets are limited to the specific knowledge from task-oriented datasets and do not fully cover the fundamental characteristics of molecules, hindering their abilities as general-purpose molecular assistants. To address this issue, we propose Mol-LLaMA, a large molecular language model that grasps the general knowledge centered on molecules via multi-modal instruction tuning. To this end, we design key data types that encompass the fundamental features of molecules, incorporating essential knowledge from molecular structures. In addition, to improve understanding of molecular features, we introduce a module that integrates complementary information from different molecular encoders, leveraging the distinct advantages of different molecular representations. Our experimental results demonstrate that Mol-LLaMA is capable of comprehending the general features of molecules and generating relevant responses to users' queries with detailed explanations, implying its potential as a general-purpose assistant for molecular analysis.

Recent advancements in open-source code large language models (LLMs) have demonstrated remarkable coding abilities by fine-tuning on the data generated from powerful closed-source LLMs such as GPT-3.5 and GPT-4 for instruction tuning. This paper explores how to further improve an instruction-tuned code LLM by generating data from itself rather than querying closed-source LLMs. Our key observation is the misalignment between the translation of formal and informal languages: translating formal language (i.e., code) to informal language (i.e., natural language) is more straightforward than the reverse. Based on this observation, we propose INVERSE-INSTRUCT, which summarizes instructions from code snippets instead of the reverse. Specifically, given an instruction tuning corpus for code and the resulting instruction-tuned code LLM, we ask the code LLM to generate additional high-quality instructions for the original corpus through code summarization and self-evaluation. Then, we fine-tune the base LLM on the combination of the original corpus and the self-generated one, which yields a stronger instruction-tuned LLM. We present a series of code LLMs named InverseCoder, which surpasses the performance of the original code LLMs on a wide range of benchmarks, including Python text-to-code generation, multilingual coding, and data-science code generation.

Recent advances in Multi-modal Large Language Models (MLLMs), such as LLaVA-series models, are driven by massive machine-generated instruction-following data tuning. Such automatic instruction collection pipelines, however, inadvertently introduce significant variability in data quality. This paper introduces a novel instruction curation algorithm, derived from two unique perspectives, human and LLM preference alignment, to compress this vast corpus of machine-generated multimodal instructions to a compact and high-quality form: (i) For human preference alignment, we have collected a machine-generated multimodal instruction dataset and established a comprehensive set of both subjective and objective criteria to guide the data quality assessment critically from human experts. By doing so, a reward model was trained on the annotated dataset to internalize the nuanced human understanding of instruction alignment. (ii) For LLM preference alignment, given the instruction selected by the reward model, we propose leveraging the inner LLM used in MLLM to align the writing style of visual instructions with that of the inner LLM itself, resulting in LLM-aligned instruction improvement. Extensive experiments demonstrate that we can maintain or even improve model performance by compressing synthetic multimodal instructions by up to 90%. Impressively, by aggressively reducing the total training sample size from 158k to 14k (9times smaller), our model consistently outperforms its full-size dataset counterpart across various MLLM benchmarks. Our project is available at https://github.com/DCDmllm/Align2LLaVA.

Controllable text generation is a fundamental aspect of natural language generation, with numerous methods proposed for different constraint types. However, these approaches often require significant architectural or decoding modifications, making them challenging to apply to additional constraints or resolve different constraint combinations. To address this, our paper introduces Regular Expression Instruction (REI), which utilizes an instruction-based mechanism to fully exploit regular expressions' advantages to uniformly model diverse constraints. Specifically, our REI supports all popular fine-grained controllable generation constraints, i.e., lexical, positional, and length, as well as their complex combinations, via regular expression-style instructions. Our method only requires fine-tuning on medium-scale language models or few-shot, in-context learning on large language models, and requires no further adjustment when applied to various constraint combinations. Experiments demonstrate that our straightforward approach yields high success rates and adaptability to various constraints while maintaining competitiveness in automatic metrics and outperforming most previous baselines.

Instruction tuning large language model (LLM) on image-text pairs has achieved unprecedented vision-language multimodal abilities. However, their vision-language alignments are only built on image-level, the lack of region-level alignment limits their advancements to fine-grained multimodal understanding. In this paper, we propose instruction tuning on region-of-interest. The key design is to reformulate the bounding box as the format of spatial instruction. The interleaved sequences of visual features extracted by the spatial instruction and the language embedding are input to LLM, and trained on the transformed region-text data in instruction tuning format. Our region-level vision-language model, termed as GPT4RoI, brings brand new conversational and interactive experience beyond image-level understanding. (1) Controllability: Users can interact with our model by both language and spatial instructions to flexibly adjust the detail level of the question. (2) Capacities: Our model supports not only single-region spatial instruction but also multi-region. This unlocks more region-level multimodal capacities such as detailed region caption and complex region reasoning. (3) Composition: Any off-the-shelf object detector can be a spatial instruction provider so as to mine informative object attributes from our model, like color, shape, material, action, relation to other objects, etc. The code, data, and demo can be found at https://github.com/jshilong/GPT4RoI.

We report a mixture of expert strategy to create fine-tuned large language models using a deep layer-wise token-level approach based on low-rank adaptation (LoRA). Starting with a set of pre-trained LoRA adapters, we propose a gating strategy that uses the hidden states to dynamically mix adapted layers, allowing the resulting X-LoRA model to draw upon different capabilities and create never-before-used deep layer-wise combinations of adaptations are established to solve specific tasks. The design is inspired by the biological principles of universality and diversity, where neural network building blocks are reused in different hierarchical manifestations. Hence, the X-LoRA model can be easily implemented for any existing large language model (LLM) without a need for modifications of the underlying structure. We develop a tailored X-LoRA model that offers scientific capabilities including forward/inverse analysis tasks and enhanced reasoning capability, focused on biomaterial analysis, protein mechanics and design. The impact of this work include access to readily expandable, adaptable and changeable models with strong domain knowledge and the capability to integrate across areas of knowledge. With the X-LoRA model featuring experts in biology, mathematics, reasoning, bio-inspired materials, mechanics and materials, chemistry, and protein mechanics we conduct a series of physics-focused case studies. We examine knowledge recall, protein mechanics forward/inverse tasks, protein design, and adversarial agentic modeling including ontological knowledge graphs. The model is capable not only of making quantitative predictions of nanomechanical properties of proteins, but also reasons over the results and correctly predicts likely mechanisms that explain distinct molecular behaviors.

Despite the promising progress in multi-modal tasks, current large multi-modal models (LMM) are prone to hallucinating inconsistent descriptions with respect to the associated image and human instructions. This paper addresses this issue by introducing the first large and diverse visual instruction tuning dataset, named Large-scale Robust Visual (LRV)-Instruction. Our dataset consists of 120k visual instructions generated by GPT4, covering 16 vision-and-language tasks with open-ended instructions and answers. Unlike existing studies that primarily focus on positive instruction samples, we design LRV-Instruction to include both positive and negative instructions for more robust visual instruction tuning. Our negative instructions are designed at two semantic levels: (i) Nonexistent Element Manipulation and (ii) Existent Element Manipulation. To efficiently measure the hallucination generated by LMMs, we propose GPT4-Assisted Visual Instruction Evaluation (GAVIE), a novel approach to evaluate visual instruction tuning without the need for human-annotated groundtruth answers and can adapt to diverse instruction formats. We conduct comprehensive experiments to investigate the hallucination of LMMs. Our results demonstrate that existing LMMs exhibit significant hallucination when presented with our negative instructions, particularly with Existent Element Manipulation instructions. Moreover, by finetuning MiniGPT4 on LRV-Instruction, we successfully mitigate hallucination while improving performance on public datasets using less training data compared to state-of-the-art methods. Additionally, we observed that a balanced ratio of positive and negative instances in the training data leads to a more robust model. Our project link is available at https://fuxiaoliu.github.io/LRV/.

Motivation: Ab initio protein docking represents a major challenge for optimizing a noisy and costly "black box"-like function in a high-dimensional space. Despite progress in this field, there is no docking method available for rigorous uncertainty quantification (UQ) of its solution quality (e.g. interface RMSD or iRMSD). Results: We introduce a novel algorithm, Bayesian Active Learning (BAL), for optimization and UQ of such black-box functions and flexible protein docking. BAL directly models the posterior distribution of the global optimum (or native structures for protein docking) with active sampling and posterior estimation iteratively feeding each other. Furthermore, we use complex normal modes to represent a homogeneous Euclidean conformation space suitable for high-dimension optimization and construct funnel-like energy models for encounter complexes. Over a protein docking benchmark set and a CAPRI set including homology docking, we establish that BAL significantly improve against both starting points by rigid docking and refinements by particle swarm optimization, providing for one third targets a top-3 near-native prediction. BAL also generates tight confidence intervals with half range around 25% of iRMSD and confidence level at 85%. Its estimated probability of a prediction being native or not achieves binary classification AUROC at 0.93 and AUPRC over 0.60 (compared to 0.14 by chance); and also found to help ranking predictions. To the best of our knowledge, this study represents the first uncertainty quantification solution for protein docking, with theoretical rigor and comprehensive assessment. Source codes are available at https://github.com/Shen-Lab/BAL.

Evaluating instruction following capabilities for multimodal, multi-turn dialogue is challenging. With potentially multiple instructions in the input model context, the task is time-consuming for human raters and we show LLM based judges are biased towards answers from the same model. We propose MMMT-IF, an image based multi-turn Q&A evaluation set with added global instructions between questions, constraining the answer format. This challenges models to retrieve instructions dispersed across long dialogues and reason under instruction constraints. All instructions are objectively verifiable through code execution. We introduce the Programmatic Instruction Following (PIF) metric to measure the fraction of the instructions that are correctly followed while performing a reasoning task. The PIF-N-K set of metrics further evaluates robustness by measuring the fraction of samples in a corpus where, for each sample, at least K out of N generated model responses achieve a PIF score of one. The PIF metric aligns with human instruction following ratings, showing 60 percent correlation. Experiments show Gemini 1.5 Pro, GPT-4o, and Claude 3.5 Sonnet, have a PIF metric that drops from 0.81 on average at turn 1 across the models, to 0.64 at turn 20. Across all turns, when each response is repeated 4 times (PIF-4-4), GPT-4o and Gemini successfully follow all instructions only 11% of the time. When all the instructions are also appended to the end of the model input context, the PIF metric improves by 22.3 points on average, showing that the challenge with the task lies not only in following the instructions, but also in retrieving the instructions spread out in the model context. We plan to open source the MMMT-IF dataset and metric computation code.

How can we design protein sequences folding into the desired structures effectively and efficiently? AI methods for structure-based protein design have attracted increasing attention in recent years; however, few methods can simultaneously improve the accuracy and efficiency due to the lack of expressive features and autoregressive sequence decoder. To address these issues, we propose PiFold, which contains a novel residue featurizer and PiGNN layers to generate protein sequences in a one-shot way with improved recovery. Experiments show that PiFold could achieve 51.66\% recovery on CATH 4.2, while the inference speed is 70 times faster than the autoregressive competitors. In addition, PiFold achieves 58.72\% and 60.42\% recovery scores on TS50 and TS500, respectively. We conduct comprehensive ablation studies to reveal the role of different types of protein features and model designs, inspiring further simplification and improvement. The PyTorch code is available at https://github.com/A4Bio/PiFold{GitHub}.

In recent years, large language models (LLMs) have achieved state-of-the-art results in various biological sequence analysis tasks, such as sequence classification, structure prediction, and function prediction. Similar to advancements in AI for other scientific fields, deeper research into biological LLMs has begun to focus on using these models to rediscover important existing biological laws or uncover entirely new patterns in biological sequences.This study leverages GPT-like LLMs to utilize language transfer capabilities to rediscover the genetic code rules of the central dogma. In our experimental design, we transformed the central dogma into a binary classification problem of aligning DNA sequences with protein sequences, where positive examples are matching DNA and protein sequences, and negative examples are non-matching pairs.We first trained a GPT-2 model from scratch using a dataset comprising protein sequences, DNA sequences, and sequences from languages such as English and Chinese. Subsequently, we fine-tuned the model using the English similarity judgment dataset from PAWS-X. When tested on a dataset for DNA and protein sequence alignment judgment, the fine-tuned model achieved a classification accuracy of 76%. The study also analyzed factors contributing to this zero-shot capability, including model training stability and types of training data.This research demonstrates that LLMs can, through the transfer of natural language capabilities and solely relying on the analysis of sequences themselves, rediscover the central dogma without prior knowledge of it. This study opens a new door for AI-driven biological research.

Large Language Models (LLMs) have substantially driven scientific progress in various domains, and many papers have demonstrated their ability to tackle complex problems with creative solutions. Our paper introduces a new foundation model, nach0, capable of solving various chemical and biological tasks: biomedical question answering, named entity recognition, molecular generation, molecular synthesis, attributes prediction, and others. nach0 is a multi-domain and multi-task encoder-decoder LLM pre-trained on unlabeled text from scientific literature, patents, and molecule strings to incorporate a range of chemical and linguistic knowledge. We employed instruction tuning, where specific task-related instructions are utilized to fine-tune nach0 for the final set of tasks. To train nach0 effectively, we leverage the NeMo framework, enabling efficient parallel optimization of both base and large model versions. Extensive experiments demonstrate that our model outperforms state-of-the-art baselines on single-domain and cross-domain tasks. Furthermore, it can generate high-quality outputs in molecular and textual formats, showcasing its effectiveness in multi-domain setups.

Existing research on instruction following largely focuses on tasks with simple instructions and short responses. In this work, we explore multi-constraint instruction following for generating long-form text. We create Suri, a dataset with 20K human-written long-form texts paired with LLM-generated backtranslated instructions that contain multiple complex constraints. Because of prohibitive challenges associated with collecting human preference judgments on long-form texts, preference-tuning algorithms such as DPO are infeasible in our setting; thus, we propose Instructional ORPO (I-ORPO), an alignment method based on the ORPO algorithm. Instead of receiving negative feedback from dispreferred responses, I-ORPO obtains negative feedback from synthetically corrupted instructions generated by an LLM. Using Suri, we perform supervised and I-ORPO fine-tuning on Mistral-7b-Instruct-v0.2. The resulting models, Suri-SFT and Suri-I-ORPO, generate significantly longer texts (~5K tokens) than base models without significant quality deterioration. Our human evaluation shows that while both SFT and I-ORPO models satisfy most constraints, Suri-I-ORPO generations are generally preferred for their coherent and informative incorporation of the constraints. We release our code at https://github.com/chtmp223/suri.

Intermediate reasoning or acting steps have successfully improved large language models (LLMs) for handling various downstream natural language processing (NLP) tasks. When applying LLMs for code generation, recent works mainly focus on directing the models to articulate intermediate natural-language reasoning steps, as in chain-of-thought (CoT) prompting, and then output code with the natural language or other structured intermediate steps. However, such output is not suitable for code translation or generation tasks since the standard CoT has different logical structures and forms of expression with the code. In this work, we introduce the universal code (UniCode) as the intermediate representation. It is a description of algorithm steps using a mix of conventions of programming languages, such as assignment operator, conditional operator, and loop. Hence, we collect an instruction dataset UniCoder-Instruct to train our model UniCoder on multi-task learning objectives. UniCoder-Instruct comprises natural-language questions, code solutions, and the corresponding universal code. The alignment between the intermediate universal code representation and the final code solution significantly improves the quality of the generated code. The experimental results demonstrate that UniCoder with the universal code significantly outperforms the previous prompting methods by a large margin, showcasing the effectiveness of the structural clues in pseudo-code.

Protein folding is the intricate process by which a linear sequence of amino acids self-assembles into a unique three-dimensional structure. Protein folding kinetics is the study of pathways and time-dependent mechanisms a protein undergoes when it folds. Understanding protein kinetics is essential as a protein needs to fold correctly for it to perform its biological functions optimally, and a misfolded protein can sometimes be contorted into shapes that are not ideal for a cellular environment giving rise to many degenerative, neuro-degenerative disorders and amyloid diseases. Monitoring at-risk individuals and detecting protein discrepancies in a protein's folding kinetics at the early stages could majorly result in public health benefits, as preventive measures can be taken. This research proposes an efficient pipeline for predicting protein folding kinetics with high accuracy and low memory footprint. The deployed machine learning (ML) model outperformed the state-of-the-art ML models by 4.8% in terms of accuracy while consuming 327x lesser memory and being 7.3% faster.

Language Models (LMs) have greatly influenced diverse domains. However, their inherent limitation in comprehending 3D molecular structures has considerably constrained their potential in the biomolecular domain. To bridge this gap, we focus on 3D molecule-text interpretation, and propose 3D-MoLM: 3D-Molecular Language Modeling. Specifically, 3D-MoLM enables an LM to interpret and analyze 3D molecules by equipping the LM with a 3D molecular encoder. This integration is achieved by a 3D molecule-text projector, bridging the 3D molecular encoder's representation space and the LM's input space. Moreover, to enhance 3D-MoLM's ability of cross-modal molecular understanding and instruction following, we meticulously curated a 3D molecule-centric instruction tuning dataset -- 3D-MoIT. Through 3D molecule-text alignment and 3D molecule-centric instruction tuning, 3D-MoLM establishes an integration of 3D molecular encoder and LM. It significantly surpasses existing baselines on downstream tasks, including molecule-text retrieval, molecule captioning, and more challenging open-text molecular QA tasks, especially focusing on 3D-dependent properties.

Antibodies are proteins produced by the immune system that can identify and neutralise a wide variety of antigens with high specificity and affinity, and constitute the most successful class of biotherapeutics. With the advent of next-generation sequencing, billions of antibody sequences have been collected in recent years, though their application in the design of better therapeutics has been constrained by the sheer volume and complexity of the data. To address this challenge, we present IgBert and IgT5, the best performing antibody-specific language models developed to date which can consistently handle both paired and unpaired variable region sequences as input. These models are trained comprehensively using the more than two billion unpaired sequences and two million paired sequences of light and heavy chains present in the Observed Antibody Space dataset. We show that our models outperform existing antibody and protein language models on a diverse range of design and regression tasks relevant to antibody engineering. This advancement marks a significant leap forward in leveraging machine learning, large scale data sets and high-performance computing for enhancing antibody design for therapeutic development.

We show that protein sequences can be thought of as sentences in natural language processing and can be parsed using the existing Quantum Natural Language framework into parameterized quantum circuits of reasonable qubits, which can be trained to solve various protein-related machine-learning problems. We classify proteins based on their subcellular locations, a pivotal task in bioinformatics that is key to understanding biological processes and disease mechanisms. Leveraging the quantum-enhanced processing capabilities, we demonstrate that Quantum Tensor Networks (QTN) can effectively handle the complexity and diversity of protein sequences. We present a detailed methodology that adapts QTN architectures to the nuanced requirements of protein data, supported by comprehensive experimental results. We demonstrate two distinct QTNs, inspired by classical recurrent neural networks (RNN) and convolutional neural networks (CNN), to solve the binary classification task mentioned above. Our top-performing quantum model has achieved a 94% accuracy rate, which is comparable to the performance of a classical model that uses the ESM2 protein language model embeddings. It's noteworthy that the ESM2 model is extremely large, containing 8 million parameters in its smallest configuration, whereas our best quantum model requires only around 800 parameters. We demonstrate that these hybrid models exhibit promising performance, showcasing their potential to compete with classical models of similar complexity.

Instruction following is one of the fundamental capabilities of large language models (LLMs). As the ability of LLMs is constantly improving, they have been increasingly applied to deal with complex human instructions in real-world scenarios. Therefore, how to evaluate the ability of complex instruction-following of LLMs has become a critical research problem. Existing benchmarks mainly focus on modeling different types of constraints in human instructions while neglecting the composition of different constraints, which is an indispensable constituent in complex instructions. To this end, we propose ComplexBench, a benchmark for comprehensively evaluating the ability of LLMs to follow complex instructions composed of multiple constraints. We propose a hierarchical taxonomy for complex instructions, including 4 constraint types, 19 constraint dimensions, and 4 composition types, and manually collect a high-quality dataset accordingly. To make the evaluation reliable, we augment LLM-based evaluators with rules to effectively verify whether generated texts can satisfy each constraint and composition. Furthermore, we obtain the final evaluation score based on the dependency structure determined by different composition types. ComplexBench identifies significant deficiencies in existing LLMs when dealing with complex instructions with multiple constraints composition.

Instruction tuning is instrumental in enabling Large Language Models~(LLMs) to follow user instructions to complete various open-domain tasks. The success of instruction tuning depends on the availability of high-quality instruction data. Owing to the exorbitant cost and substandard quality of human annotation, recent works have been deeply engaged in the exploration of the utilization of powerful closed-source models to generate instruction data automatically. However, these methods carry potential risks arising from the usage requirements of powerful closed-source models, which strictly forbid the utilization of their outputs to develop machine learning models. To deal with this problem, in this work, we explore alternative approaches to generate high-quality instruction data that do not rely on closed-source models. Our exploration includes an investigation of various existing instruction generation methods, culminating in the integration of the most efficient variant with two novel strategies to enhance the quality further. Evaluation results from two benchmarks and the GPT-4 model demonstrate the effectiveness of our generated instruction data, which can outperform Alpaca, a method reliant on closed-source models. We hope that more progress can be achieved in generating high-quality instruction data without using closed-source models.

Recent advancements in biological research leverage the integration of molecules, proteins, and natural language to enhance drug discovery. However, current models exhibit several limitations, such as the generation of invalid molecular SMILES, underutilization of contextual information, and equal treatment of structured and unstructured knowledge. To address these issues, we propose BioT5, a comprehensive pre-training framework that enriches cross-modal integration in biology with chemical knowledge and natural language associations. BioT5 utilizes SELFIES for 100% robust molecular representations and extracts knowledge from the surrounding context of bio-entities in unstructured biological literature. Furthermore, BioT5 distinguishes between structured and unstructured knowledge, leading to more effective utilization of information. After fine-tuning, BioT5 shows superior performance across a wide range of tasks, demonstrating its strong capability of capturing underlying relations and properties of bio-entities. Our code is available at https://github.com/QizhiPei/BioT5{Github}.

In human-written articles, we often leverage the subtleties of text style, such as bold and italics, to guide the attention of readers. These textual emphases are vital for the readers to grasp the conveyed information. When interacting with large language models (LLMs), we have a similar need - steering the model to pay closer attention to user-specified information, e.g., an instruction. Existing methods, however, are constrained to process plain text and do not support such a mechanism. This motivates us to introduce PASTA - Post-hoc Attention STeering Approach, a method that allows LLMs to read text with user-specified emphasis marks. To this end, PASTA identifies a small subset of attention heads and applies precise attention reweighting on them, directing the model attention to user-specified parts. Like prompting, PASTA is applied at inference time and does not require changing any model parameters. Experiments demonstrate that PASTA can substantially enhance an LLM's ability to follow user instructions or integrate new knowledge from user inputs, leading to a significant performance improvement on a variety of tasks, e.g., an average accuracy improvement of 22% for LLAMA-7B. Our code is publicly available at https://github.com/QingruZhang/PASTA .

Multiple Sequence Alignment (MSA) plays a pivotal role in unveiling the evolutionary trajectories of protein families. The accuracy of protein structure predictions is often compromised for protein sequences that lack sufficient homologous information to construct high quality MSA. Although various methods have been proposed to generate virtual MSA under these conditions, they fall short in comprehensively capturing the intricate coevolutionary patterns within MSA or require guidance from external oracle models. Here we introduce MSAGPT, a novel approach to prompt protein structure predictions via MSA generative pretraining in the low MSA regime. MSAGPT employs a simple yet effective 2D evolutionary positional encoding scheme to model complex evolutionary patterns. Endowed by this, its flexible 1D MSA decoding framework facilitates zero or few shot learning. Moreover, we demonstrate that leveraging the feedback from AlphaFold2 can further enhance the model capacity via Rejective Fine tuning (RFT) and Reinforcement Learning from AF2 Feedback (RLAF). Extensive experiments confirm the efficacy of MSAGPT in generating faithful virtual MSA to enhance the structure prediction accuracy. The transfer learning capabilities also highlight its great potential for facilitating other protein tasks.

Biological processes, functions, and properties are intricately linked to the ensemble of protein conformations, rather than being solely determined by a single stable conformation. In this study, we have developed P2DFlow, a generative model based on SE(3) flow matching, to predict the structural ensembles of proteins. We specifically designed a valuable prior for the flow process and enhanced the model's ability to distinguish each intermediate state by incorporating an additional dimension to describe the ensemble data, which can reflect the physical laws governing the distribution of ensembles, so that the prior knowledge can effectively guide the generation process. When trained and evaluated on the MD datasets of ATLAS, P2DFlow outperforms other baseline models on extensive experiments, successfully capturing the observable dynamic fluctuations as evidenced in crystal structure and MD simulations. As a potential proxy agent for protein molecular simulation, the high-quality ensembles generated by P2DFlow could significantly aid in understanding protein functions across various scenarios. Code is available at https://github.com/BLEACH366/P2DFlow

Existing visual parsers for molecule diagrams translate pixel-based raster images such as PNGs to chemical structure representations (e.g., SMILES). However, PDFs created by word processors including LaTeX and Word provide explicit locations and shapes for characters, lines, and polygons. We extract symbols from born-digital PDF molecule images and then apply simple graph transformations to capture both visual and chemical structure in editable ChemDraw files (CDXML). Our fast ( PDF rightarrow visual graph rightarrow chemical graph ) pipeline does not require GPUs, Optical Character Recognition (OCR) or vectorization. We evaluate on standard benchmarks using SMILES strings, along with a novel evaluation that provides graph-based metrics and error compilation using LgEval. The geometric information in born-digital PDFs produces a highly accurate parser, motivating generating training data for visual parsers that recognize from raster images, with extracted graphics, visual structure, and chemical structure as annotations. To do this we render SMILES strings in Indigo, parse molecule structure, and then validate recognized structure to select correct files.

We introduce the new task of generating Illustrated Instructions, i.e., visual instructions customized to a user's needs. We identify desiderata unique to this task, and formalize it through a suite of automatic and human evaluation metrics, designed to measure the validity, consistency, and efficacy of the generations. We combine the power of large language models (LLMs) together with strong text-to-image generation diffusion models to propose a simple approach called StackedDiffusion, which generates such illustrated instructions given text as input. The resulting model strongly outperforms baseline approaches and state-of-the-art multimodal LLMs; and in 30% of cases, users even prefer it to human-generated articles. Most notably, it enables various new and exciting applications far beyond what static articles on the web can provide, such as personalized instructions complete with intermediate steps and pictures in response to a user's individual situation.

Instruction tuning unlocks the superior capability of Large Language Models (LLM) to interact with humans. Furthermore, recent instruction-following datasets include images as visual inputs, collecting responses for image-based instructions. However, visual instruction-tuned models cannot comprehend textual details within images well. This work enhances the current visual instruction tuning pipeline with text-rich images (e.g., movie posters, book covers, etc.). Specifically, we first use publicly available OCR tools to collect results on 422K text-rich images from the LAION dataset. Moreover, we prompt text-only GPT-4 with recognized texts and image captions to generate 16K conversations, each containing question-answer pairs for text-rich images. By combining our collected data with previous multi-modal instruction-following data, our model, LLaVAR, substantially improves the LLaVA model's capability on text-based VQA datasets (up to 20% accuracy improvement) while achieving an accuracy of 91.42% on ScienceQA. The GPT-4-based instruction-following evaluation also demonstrates the improvement of our model on both natural images and text-rich images. Through qualitative analysis, LLaVAR shows promising interaction (e.g., reasoning, writing, and elaboration) skills with humans based on the latest real-world online content that combines text and images. We make our code/data/models publicly available at https://llavar.github.io/.

mRNA-based vaccines have become a major focus in the pharmaceutical industry. The coding sequence as well as the Untranslated Regions (UTRs) of an mRNA can strongly influence translation efficiency, stability, degradation, and other factors that collectively determine a vaccine's effectiveness. However, optimizing mRNA sequences for those properties remains a complex challenge. Existing deep learning models often focus solely on coding region optimization, overlooking the UTRs. We present Helix-mRNA, a structured state-space-based and attention hybrid model to address these challenges. In addition to a first pre-training, a second pre-training stage allows us to specialise the model with high-quality data. We employ single nucleotide tokenization of mRNA sequences with codon separation, ensuring prior biological and structural information from the original mRNA sequence is not lost. Our model, Helix-mRNA, outperforms existing methods in analysing both UTRs and coding region properties. It can process sequences 6x longer than current approaches while using only 10% of the parameters of existing foundation models. Its predictive capabilities extend to all mRNA regions. We open-source the model (https://github.com/helicalAI/helical) and model weights (https://huggingface.co/helical-ai/helix-mRNA).

Traditional computer vision generally solves each single task independently by a dedicated model with the task instruction implicitly designed in the model architecture, arising two limitations: (1) it leads to task-specific models, which require multiple models for different tasks and restrict the potential synergies from diverse tasks; (2) it leads to a pre-defined and fixed model interface that has limited interactivity and adaptability in following user' task instructions. To address them, Visual Instruction Tuning (VIT) has been intensively studied recently, which finetunes a large vision model with language as task instructions, aiming to learn from a wide range of vision tasks described by language instructions a general-purpose multimodal model that can follow arbitrary instructions and thus solve arbitrary tasks specified by the user. This work aims to provide a systematic review of visual instruction tuning, covering (1) the background that presents computer vision task paradigms and the development of VIT; (2) the foundations of VIT that introduce commonly used network architectures, visual instruction tuning frameworks and objectives, and evaluation setups and tasks; (3) the commonly used datasets in visual instruction tuning and evaluation; (4) the review of existing VIT methods that categorizes them with a taxonomy according to both the studied vision task and the method design and highlights the major contributions, strengths, and shortcomings of them; (5) the comparison and discussion of VIT methods over various instruction-following benchmarks; (6) several challenges, open directions and possible future works in visual instruction tuning research.

The regulation of various cellular processes heavily relies on the protein complexes within a living cell, necessitating a comprehensive understanding of their three-dimensional structures to elucidate the underlying mechanisms. While neural docking techniques have exhibited promising outcomes in binary protein docking, the application of advanced neural architectures to multimeric protein docking remains uncertain. This study introduces SyNDock, an automated framework that swiftly assembles precise multimeric complexes within seconds, showcasing performance that can potentially surpass or be on par with recent advanced approaches. SyNDock possesses several appealing advantages not present in previous approaches. Firstly, SyNDock formulates multimeric protein docking as a problem of learning global transformations to holistically depict the placement of chain units of a complex, enabling a learning-centric solution. Secondly, SyNDock proposes a trainable two-step SE(3) algorithm, involving initial pairwise transformation and confidence estimation, followed by global transformation synchronization. This enables effective learning for assembling the complex in a globally consistent manner. Lastly, extensive experiments conducted on our proposed benchmark dataset demonstrate that SyNDock outperforms existing docking software in crucial performance metrics, including accuracy and runtime. For instance, it achieves a 4.5% improvement in performance and a remarkable millionfold acceleration in speed.

Advancements in DNA sequencing technologies have significantly improved our ability to decode genomic sequences. However, the prediction and interpretation of these sequences remain challenging due to the intricate nature of genetic material. Large language models (LLMs) have introduced new opportunities for biological sequence analysis. Recent developments in genomic language models have underscored the potential of LLMs in deciphering DNA sequences. Nonetheless, existing models often face limitations in robustness and application scope, primarily due to constraints in model structure and training data scale. To address these limitations, we present GENERator, a generative genomic foundation model featuring a context length of 98k base pairs (bp) and 1.2B parameters. Trained on an expansive dataset comprising 386B bp of eukaryotic DNA, the GENERator demonstrates state-of-the-art performance across both established and newly proposed benchmarks. The model adheres to the central dogma of molecular biology, accurately generating protein-coding sequences that translate into proteins structurally analogous to known families. It also shows significant promise in sequence optimization, particularly through the prompt-responsive generation of promoter sequences with specific activity profiles. These capabilities position the GENERator as a pivotal tool for genomic research and biotechnological advancement, enhancing our ability to interpret and predict complex biological systems and enabling precise genomic interventions.

Foundation models have revolutionized natural language processing and artificial intelligence, significantly enhancing how machines comprehend and generate human languages. Inspired by the success of these foundation models, researchers have developed foundation models for individual scientific domains, including small molecules, materials, proteins, DNA, and RNA. However, these models are typically trained in isolation, lacking the ability to integrate across different scientific domains. Recognizing that entities within these domains can all be represented as sequences, which together form the "language of nature", we introduce Nature Language Model (briefly, NatureLM), a sequence-based science foundation model designed for scientific discovery. Pre-trained with data from multiple scientific domains, NatureLM offers a unified, versatile model that enables various applications including: (i) generating and optimizing small molecules, proteins, RNA, and materials using text instructions; (ii) cross-domain generation/design, such as protein-to-molecule and protein-to-RNA generation; and (iii) achieving state-of-the-art performance in tasks like SMILES-to-IUPAC translation and retrosynthesis on USPTO-50k. NatureLM offers a promising generalist approach for various scientific tasks, including drug discovery (hit generation/optimization, ADMET optimization, synthesis), novel material design, and the development of therapeutic proteins or nucleotides. We have developed NatureLM models in different sizes (1 billion, 8 billion, and 46.7 billion parameters) and observed a clear improvement in performance as the model size increases.

Training large language models (LLM) with open-domain instruction following data brings colossal success. However, manually creating such instruction data is very time-consuming and labor-intensive. Moreover, humans may struggle to produce high-complexity instructions. In this paper, we show an avenue for creating large amounts of instruction data with varying levels of complexity using LLM instead of humans. Starting with an initial set of instructions, we use our proposed Evol-Instruct to rewrite them step by step into more complex instructions. Then, we mix all generated instruction data to fine-tune LLaMA. We call the resulting model WizardLM. Human evaluations on a complexity-balanced test bed show that instructions from Evol-Instruct are superior to human-created ones. By analyzing the human evaluation results of the high complexity part, we demonstrate that outputs from our WizardLM model are preferred to outputs from OpenAI ChatGPT. Even though WizardLM still lags behind ChatGPT in some aspects, our findings suggest that fine-tuning with AI-evolved instructions is a promising direction for enhancing large language models. Our codes and generated data are public at https://github.com/nlpxucan/WizardLM

High-quality, large-scale instructions are crucial for aligning large language models (LLMs), however, there is a severe shortage of instruction in the field of natural language understanding (NLU). Previous works on constructing NLU instructions mainly focus on information extraction (IE), neglecting tasks such as machine reading comprehension, question answering, and text classification. Furthermore, the lack of diversity in the data has led to a decreased generalization ability of trained LLMs in other NLU tasks and a noticeable decline in the fundamental model's general capabilities. To address this issue, we propose Hum, a large-scale, high-quality synthetic instruction corpus for NLU tasks, designed to enhance the NLU capabilities of LLMs. Specifically, Hum includes IE (either close IE or open IE), machine reading comprehension, text classification, and instruction generalist tasks, thereby enriching task diversity. Additionally, we introduce a human-LLMs collaborative mechanism to synthesize instructions, which enriches instruction diversity by incorporating guidelines, preference rules, and format variants. We conduct extensive experiments on 5 NLU tasks and 28 general capability evaluation datasets for LLMs. Experimental results show that Hum enhances the NLU capabilities of six LLMs by an average of 3.1\%, with no significant decline observed in other general capabilities.

This article introduces contrastive alignment instructions (AlignInstruct) to address two challenges in machine translation (MT) on large language models (LLMs). One is the expansion of supported languages to previously unseen ones. The second relates to the lack of data in low-resource languages. Model fine-tuning through MT instructions (MTInstruct) is a straightforward approach to the first challenge. However, MTInstruct is limited by weak cross-lingual signals inherent in the second challenge. AlignInstruct emphasizes cross-lingual supervision via a cross-lingual discriminator built using statistical word alignments. Our results based on fine-tuning the BLOOMZ models (1b1, 3b, and 7b1) in up to 24 unseen languages showed that: (1) LLMs can effectively translate unseen languages using MTInstruct; (2) AlignInstruct led to consistent improvements in translation quality across 48 translation directions involving English; (3) Discriminator-based instructions outperformed their generative counterparts as cross-lingual instructions; (4) AlignInstruct improved performance in 30 zero-shot directions.

Building generalist models has recently demonstrated remarkable capabilities in diverse scientific domains. Within the realm of molecular learning, several studies have explored unifying diverse tasks across diverse domains. However, negative conflicts and interference between molecules and knowledge from different domain may have a worse impact in threefold. First, conflicting molecular representations can lead to optimization difficulties for the models. Second, mixing and scaling up training data across diverse tasks is inherently challenging. Third, the computational cost of refined pretraining is prohibitively high. To address these limitations, this paper presents Omni-Mol, a scalable and unified LLM-based framework for direct instruction tuning. Omni-Mol builds on three key components to tackles conflicts: (1) a unified encoding mechanism for any task input; (2) an active-learning-driven data selection strategy that significantly reduces dataset size; (3) a novel design of the adaptive gradient stabilization module and anchor-and-reconcile MoE framework that ensures stable convergence. Experimentally, Omni-Mol achieves state-of-the-art performance across 15 molecular tasks, demonstrates the presence of scaling laws in the molecular domain, and is supported by extensive ablation studies and analyses validating the effectiveness of its design. The code and weights of the powerful AI-driven chemistry generalist are open-sourced at: https://anonymous.4open.science/r/Omni-Mol-8EDB.

Large language models (LLMs) have shown impressive ability for open-domain NLP tasks. However, LLMs are sometimes too footloose for natural language understanding (NLU) tasks which always have restricted output and input format. Their performances on NLU tasks are highly related to prompts or demonstrations and are shown to be poor at performing several representative NLU tasks, such as event extraction and entity typing. To this end, we present SeqGPT, a bilingual (i.e., English and Chinese) open-source autoregressive model specially enhanced for open-domain natural language understanding. We express all NLU tasks with two atomic tasks, which define fixed instructions to restrict the input and output format but still ``open'' for arbitrarily varied label sets. The model is first instruction-tuned with extremely fine-grained labeled data synthesized by ChatGPT and then further fine-tuned by 233 different atomic tasks from 152 datasets across various domains. The experimental results show that SeqGPT has decent classification and extraction ability, and is capable of performing language understanding tasks on unseen domains. We also conduct empirical studies on the scaling of data and model size as well as on the transfer across tasks. Our model is accessible at https://github.com/Alibaba-NLP/SeqGPT.

Large Language Models (LLMs) are susceptible to security and safety threats, such as prompt injection, prompt extraction, and harmful requests. One major cause of these vulnerabilities is the lack of an instruction hierarchy. Modern LLM architectures treat all inputs equally, failing to distinguish between and prioritize various types of instructions, such as system messages, user prompts, and data. As a result, lower-priority user prompts may override more critical system instructions, including safety protocols. Existing approaches to achieving instruction hierarchy, such as delimiters and instruction-based training, do not address this issue at the architectural level. We introduce the Instructional Segment Embedding (ISE) technique, inspired by BERT, to modern large language models, which embeds instruction priority information directly into the model. This approach enables models to explicitly differentiate and prioritize various instruction types, significantly improving safety against malicious prompts that attempt to override priority rules. Our experiments on the Structured Query and Instruction Hierarchy benchmarks demonstrate an average robust accuracy increase of up to 15.75% and 18.68%, respectively. Furthermore, we observe an improvement in instruction-following capability of up to 4.1% evaluated on AlpacaEval. Overall, our approach offers a promising direction for enhancing the safety and effectiveness of LLM architectures.

Large-scale datasets are essential to modern day deep learning. Advocates argue that understanding these methods requires dataset transparency (e.g. "dataset curation, motivation, composition, collection process, etc..."). However, almost no one has suggested the release of the detailed definitions and visual category examples provided to annotators - information critical to understanding the structure of the annotations present in each dataset. These labels are at the heart of public datasets, yet few datasets include the instructions that were used to generate them. We introduce a new task, Labeling Instruction Generation, to address missing publicly available labeling instructions. In Labeling Instruction Generation, we take a reasonably annotated dataset and: 1) generate a set of examples that are visually representative of each category in the dataset; 2) provide a text label that corresponds to each of the examples. We introduce a framework that requires no model training to solve this task and includes a newly created rapid retrieval system that leverages a large, pre-trained vision and language model. This framework acts as a proxy to human annotators that can help to both generate a final labeling instruction set and evaluate its quality. Our framework generates multiple diverse visual and text representations of dataset categories. The optimized instruction set outperforms our strongest baseline across 5 folds by 7.06 mAP for NuImages and 12.9 mAP for COCO.

Ligand molecule conformation generation is a critical challenge in drug discovery. Deep learning models have been developed to tackle this problem, particularly through the use of generative models in recent years. However, these models often generate conformations that lack meaningful structure and randomness due to the absence of essential side information. Examples of such side information include the chemical and geometric features of the target protein, ligand-target compound interactions, and ligand chemical properties. Without these constraints, the generated conformations may not be suitable for further selection and design of new drugs. To address this limitation, we propose a novel method for generating ligand conformations that leverage side information and incorporate flexible constraints into standard diffusion models. Drawing inspiration from the concept of message passing, we introduce ligand-target massage passing block, a mechanism that facilitates the exchange of information between target nodes and ligand nodes, thereby incorporating target node features. To capture non-covalent interactions, we introduce ligand-target compound inter and intra edges. To further improve the biological relevance of the generated conformations, we train energy models using scalar chemical features. These models guide the progress of the standard Denoising Diffusion Probabilistic Models, resulting in more biologically meaningful conformations. We evaluate the performance of SIDEGEN using the PDBBind-2020 dataset, comparing it against other methods. The results demonstrate improvements in both Aligned RMSD and Ligand RMSD evaluations. Specifically, our model outperforms GeoDiff (trained on PDBBind-2020) by 20% in terms of the median aligned RMSD metric.

The rapid advancements in transformer-based language models have revolutionized natural language processing, yet understanding the internal mechanisms of these models remains a significant challenge. This paper explores the application of sparse autoencoders (SAE) to interpret the internal representations of protein language models, specifically focusing on the ESM-2 8M parameter model. By performing a statistical analysis on each latent component's relevance to distinct protein annotations, we identify potential interpretations linked to various protein characteristics, including transmembrane regions, binding sites, and specialized motifs. We then leverage these insights to guide sequence generation, shortlisting the relevant latent components that can steer the model towards desired targets such as zinc finger domains. This work contributes to the emerging field of mechanistic interpretability in biological sequence models, offering new perspectives on model steering for sequence design.

Spider silks are remarkable materials characterized by superb mechanical properties such as strength, extensibility and lightweightedness. Yet, to date, limited models are available to fully explore sequence-property relationships for analysis and design. Here we propose a custom generative large-language model to enable design of novel spider silk protein sequences to meet complex combinations of target mechanical properties. The model, pretrained on a large set of protein sequences, is fine-tuned on ~1,000 major ampullate spidroin (MaSp) sequences for which associated fiber-level mechanical properties exist, to yield an end-to-end forward and inverse generative strategy. Performance is assessed through: (1), a novelty analysis and protein type classification for generated spidroin sequences through BLAST searches, (2) property evaluation and comparison with similar sequences, (3) comparison of molecular structures, as well as, and (4) a detailed sequence motif analyses. We generate silk sequences with property combinations that do not exist in nature, and develop a deep understanding the mechanistic roles of sequence patterns in achieving overarching key mechanical properties (elastic modulus, strength, toughness, failure strain). The model provides an efficient approach to expand the silkome dataset, facilitating further sequence-structure analyses of silks, and establishes a foundation for synthetic silk design and optimization.

Offline model-based optimization aims to maximize a black-box objective function with a static dataset of designs and their scores. In this paper, we focus on biological sequence design to maximize some sequence score. A recent approach employs bidirectional learning, combining a forward mapping for exploitation and a backward mapping for constraint, and it relies on the neural tangent kernel (NTK) of an infinitely wide network to build a proxy model. Though effective, the NTK cannot learn features because of its parametrization, and its use prevents the incorporation of powerful pre-trained Language Models (LMs) that can capture the rich biophysical information in millions of biological sequences. We adopt an alternative proxy model, adding a linear head to a pre-trained LM, and propose a linearization scheme. This yields a closed-form loss and also takes into account the biophysical information in the pre-trained LM. In addition, the forward mapping and the backward mapping play different roles and thus deserve different weights during sequence optimization. To achieve this, we train an auxiliary model and leverage its weak supervision signal via a bi-level optimization framework to effectively learn how to balance the two mappings. Further, by extending the framework, we develop the first learning rate adaptation module Adaptive-eta, which is compatible with all gradient-based algorithms for offline model-based optimization. Experimental results on DNA/protein sequence design tasks verify the effectiveness of our algorithm. Our code is available~https://anonymous.4open.science/r/BIB-ICLR2023-Submission/README.md{here.}

Fine-tuning large language models (LLMs) with a collection of large and diverse instructions has improved the model's generalization to different tasks, even for unseen tasks. However, most existing instruction datasets include only single instructions, and they struggle to follow complex instructions composed of multiple subtasks (Wang et al., 2023a). In this work, we propose a novel concept of compositional instructions called chain-of-instructions (CoI), where the output of one instruction becomes an input for the next like a chain. Unlike the conventional practice of solving single instruction tasks, our proposed method encourages a model to solve each subtask step by step until the final answer is reached. CoI-tuning (i.e., fine-tuning with CoI instructions) improves the model's ability to handle instructions composed of multiple subtasks. CoI-tuned models also outperformed baseline models on multilingual summarization, demonstrating the generalizability of CoI models on unseen composite downstream tasks.

Despite being self-supervised, protein language models have shown remarkable performance in fundamental biological tasks such as predicting impact of genetic variation on protein structure and function. The effectiveness of these models on diverse set of tasks suggests that they learn meaningful representations of fitness landscape that can be useful for downstream clinical applications. Here, we interrogate the use of these language models in characterizing known pathogenic mutations in curated, medically actionable genes through an exhaustive search of putative compensatory mutations on each variant's genetic background. Systematic analysis of the predicted effects of these compensatory mutations reveal unappreciated structural features of proteins that are missed by other structure predictors like AlphaFold. While deep mutational scan experiments provide an unbiased estimate of the mutational landscape, we encourage the community to generate and curate rescue mutation experiments to inform the design of more sophisticated co-masking strategies and leverage large language models more effectively for downstream clinical prediction tasks.

There are substantial instructional videos on the Internet, which provide us tutorials for completing various tasks. Existing instructional video datasets only focus on specific steps at the video level, lacking experiential guidelines at the task level, which can lead to beginners struggling to learn new tasks due to the lack of relevant experience. Moreover, the specific steps without guidelines are trivial and unsystematic, making it difficult to provide a clear tutorial. To address these problems, we present the GUIDE (Guideline-Guided) dataset, which contains 3.5K videos of 560 instructional tasks in 8 domains related to our daily life. Specifically, we annotate each instructional task with a guideline, representing a common pattern shared by all task-related videos. On this basis, we annotate systematic specific steps, including their associated guideline steps, specific step descriptions and timestamps. Our proposed benchmark consists of three sub-tasks to evaluate comprehension ability of models: (1) Step Captioning: models have to generate captions for specific steps from videos. (2) Guideline Summarization: models have to mine the common pattern in task-related videos and summarize a guideline from them. (3) Guideline-Guided Captioning: models have to generate captions for specific steps under the guide of guideline. We evaluate plenty of foundation models with GUIDE and perform in-depth analysis. Given the diversity and practicality of GUIDE, we believe that it can be used as a better benchmark for instructional video comprehension.

We study the problem of extrapolative controlled generation, i.e., generating sequences with attribute values beyond the range seen in training. This task is of significant importance in automated design, especially drug discovery, where the goal is to design novel proteins that are better (e.g., more stable) than existing sequences. Thus, by definition, the target sequences and their attribute values are out of the training distribution, posing challenges to existing methods that aim to directly generate the target sequence. Instead, in this work, we propose Iterative Controlled Extrapolation (ICE) which iteratively makes local edits to a sequence to enable extrapolation. We train the model on synthetically generated sequence pairs that demonstrate small improvement in the attribute value. Results on one natural language task (sentiment analysis) and two protein engineering tasks (ACE2 stability and AAV fitness) show that ICE considerably outperforms state-of-the-art approaches despite its simplicity. Our code and models are available at: https://github.com/vishakhpk/iter-extrapolation.

Instruction tuning has remarkably advanced large language models (LLMs) in understanding and responding to diverse human instructions. Despite the success in high-resource languages, its application in lower-resource ones faces challenges due to the imbalanced foundational abilities of LLMs across different languages, stemming from the uneven language distribution in their pre-training data. To tackle this issue, we propose pivot language guided generation (PLUG), an approach that utilizes a high-resource language, primarily English, as the pivot to enhance instruction tuning in lower-resource languages. It trains the model to first process instructions in the pivot language, and then produce responses in the target language. To evaluate our approach, we introduce a benchmark, X-AlpacaEval, of instructions in 4 languages (Chinese, Korean, Italian, and Spanish), each annotated by professional translators. Our approach demonstrates a significant improvement in the instruction-following abilities of LLMs by 29% on average, compared to directly responding in the target language alone. Further experiments validate the versatility of our approach by employing alternative pivot languages beyond English to assist languages where LLMs exhibit lower proficiency.

Recipe generation from food images and ingredients is a challenging task, which requires the interpretation of the information from another modality. Different from the image captioning task, where the captions usually have one sentence, cooking instructions contain multiple sentences and have obvious structures. To help the model capture the recipe structure and avoid missing some cooking details, we propose a novel framework: Decomposing Generation Networks (DGN) with structure prediction, to get more structured and complete recipe generation outputs. Specifically, we split each cooking instruction into several phases, and assign different sub-generators to each phase. Our approach includes two novel ideas: (i) learning the recipe structures with the global structure prediction component and (ii) producing recipe phases in the sub-generator output component based on the predicted structure. Extensive experiments on the challenging large-scale Recipe1M dataset validate the effectiveness of our proposed model, which improves the performance over the state-of-the-art results.

It is imperative for Large language models (LLMs) to follow instructions with elaborate requirements (i.e. Complex Instructions Following). Yet, it remains under-explored how to enhance the ability of LLMs to follow complex instructions with multiple constraints. To bridge the gap, we initially study what training data is effective in enhancing complex constraints following abilities. We found that training LLMs with instructions containing multiple constraints enhances their understanding of complex instructions, especially those with lower complexity levels. The improvement can even generalize to compositions of out-of-domain constraints. Additionally, we further propose methods addressing how to obtain and utilize the effective training data. Finally, we conduct extensive experiments to prove the effectiveness of our methods in terms of overall performance and training efficiency. We also demonstrate that our methods improve models' ability to follow instructions generally and generalize effectively across out-of-domain, in-domain, and adversarial settings, while maintaining general capabilities.

In recent decades, chemistry publications and patents have increased rapidly. A significant portion of key information is embedded in molecular structure figures, complicating large-scale literature searches and limiting the application of large language models in fields such as biology, chemistry, and pharmaceuticals. The automatic extraction of precise chemical structures is of critical importance. However, the presence of numerous Markush structures in real-world documents, along with variations in molecular image quality, drawing styles, and noise, significantly limits the performance of existing optical chemical structure recognition (OCSR) methods. We present MolParser, a novel end-to-end OCSR method that efficiently and accurately recognizes chemical structures from real-world documents, including difficult Markush structure. We use a extended SMILES encoding rule to annotate our training dataset. Under this rule, we build MolParser-7M, the largest annotated molecular image dataset to our knowledge. While utilizing a large amount of synthetic data, we employed active learning methods to incorporate substantial in-the-wild data, specifically samples cropped from real patents and scientific literature, into the training process. We trained an end-to-end molecular image captioning model, MolParser, using a curriculum learning approach. MolParser significantly outperforms classical and learning-based methods across most scenarios, with potential for broader downstream applications. The dataset is publicly available.

Understanding protein solubility is essential for their functional applications. Computational methods for predicting protein solubility are crucial for reducing experimental costs and enhancing the efficiency and success rates of protein engineering. Existing methods either construct a supervised learning scheme on small-scale datasets with manually processed physicochemical properties, or blindly apply pre-trained protein language models to extract amino acid interaction information. The scale and quality of available training datasets leave significant room for improvement in terms of accuracy and generalization. To address these research gaps, we propose \sol, a novel deep learning method that combines pre-training and fine-tuning schemes for protein solubility prediction. ProtSolM integrates information from multiple dimensions, including physicochemical properties, amino acid sequences, and protein backbone structures. Our model is trained using \data, the largest solubility dataset that we have constructed. PDBSol includes over 60,000 protein sequences and structures. We provide a comprehensive leaderboard of existing statistical learning and deep learning methods on independent datasets with computational and experimental labels. ProtSolM achieved state-of-the-art performance across various evaluation metrics, demonstrating its potential to significantly advance the accuracy of protein solubility prediction.

Instruction-following is particularly crucial for large language models (LLMs) to support diverse user requests. While existing work has made progress in aligning LLMs with human preferences, evaluating their capabilities on instruction following remains a challenge due to complexity and diversity of real-world user instructions. While existing evaluation methods focus on general skills, they suffer from two main shortcomings, i.e., lack of fine-grained task-level evaluation and reliance on singular instruction expression. To address these problems, this paper introduces DINGO, a fine-grained and diverse instruction-following evaluation dataset that has two main advantages: (1) DINGO is based on a manual annotated, fine-grained and multi-level category tree with 130 nodes derived from real-world user requests; (2) DINGO includes diverse instructions, generated by both GPT-4 and human experts. Through extensive experiments, we demonstrate that DINGO can not only provide more challenging and comprehensive evaluation for LLMs, but also provide task-level fine-grained directions to further improve LLMs.

Following multiple instructions is a crucial ability for large language models (LLMs). Evaluating this ability comes with significant challenges: (i) limited coherence between multiple instructions, (ii) positional bias where the order of instructions affects model performance, and (iii) a lack of objectively verifiable tasks. To address these issues, we introduce a benchmark designed to evaluate models' abilities to follow multiple instructions through sequential instruction following (SIFo) tasks. In SIFo, the successful completion of multiple instructions is verifiable by examining only the final instruction. Our benchmark evaluates instruction following using four tasks (text modification, question answering, mathematics, and security rule following), each assessing different aspects of sequential instruction following. Our evaluation of popular LLMs, both closed-source and open-source, shows that more recent and larger models significantly outperform their older and smaller counterparts on the SIFo tasks, validating the benchmark's effectiveness. All models struggle with following sequences of instructions, hinting at an important lack of robustness of today's language models.

Coarse-graining (CG) accelerates molecular simulations of protein dynamics by simulating sets of atoms as singular beads. Backmapping is the opposite operation of bringing lost atomistic details back from the CG representation. While machine learning (ML) has produced accurate and efficient CG simulations of proteins, fast and reliable backmapping remains a challenge. Rule-based methods produce poor all-atom geometries, needing computationally costly refinement through additional simulations. Recently proposed ML approaches outperform traditional baselines but are not transferable between proteins and sometimes generate unphysical atom placements with steric clashes and implausible torsion angles. This work addresses both issues to build a fast, transferable, and reliable generative backmapping tool for CG protein representations. We achieve generalization and reliability through a combined set of innovations: representation based on internal coordinates; an equivariant encoder/prior; a custom loss function that helps ensure local structure, global structure, and physical constraints; and expert curation of high-quality out-of-equilibrium protein data for training. Our results pave the way for out-of-the-box backmapping of coarse-grained simulations for arbitrary proteins.

The rapid evolution of artificial intelligence in drug discovery encounters challenges with generalization and extensive training, yet Large Language Models (LLMs) offer promise in reshaping interactions with complex molecular data. Our novel contribution, InstructMol, a multi-modal LLM, effectively aligns molecular structures with natural language via an instruction-tuning approach, utilizing a two-stage training strategy that adeptly combines limited domain-specific data with molecular and textual information. InstructMol showcases substantial performance improvements in drug discovery-related molecular tasks, surpassing leading LLMs and significantly reducing the gap with specialized models, thereby establishing a robust foundation for a versatile and dependable drug discovery assistant.

Large Language Models (LLMs) have showcased remarkable capabilities in following human instructions. However, recent studies have raised concerns about the robustness of LLMs when prompted with instructions combining textual adversarial samples. In this paper, drawing inspiration from recent works that LLMs are sensitive to the design of the instructions, we utilize instructions in code style, which are more structural and less ambiguous, to replace typically natural language instructions. Through this conversion, we provide LLMs with more precise instructions and strengthen the robustness of LLMs. Moreover, under few-shot scenarios, we propose a novel method to compose in-context demonstrations using both clean and adversarial samples (adversarial context method) to further boost the robustness of the LLMs. Experiments on eight robustness datasets show that our method consistently outperforms prompting LLMs with natural language instructions. For example, with gpt-3.5-turbo, our method achieves an improvement of 5.68\% in test set accuracy and a reduction of 5.66 points in Attack Success Rate (ASR).

Despite recent advancements, most computational methods for molecule optimization are constrained to single- or double-property optimization tasks and suffer from poor scalability and generalizability to novel optimization tasks. Meanwhile, Large Language Models (LLMs) demonstrate remarkable out-of-domain generalizability to novel tasks. To demonstrate LLMs' potential for molecule optimization, we introduce MoMUInstruct, the first high-quality instruction-tuning dataset specifically focused on complex multi-property molecule optimization tasks. Leveraging MoMUInstruct, we develop GeLLM^3Os, a series of instruction-tuned LLMs for molecule optimization. Extensive evaluations across 5 in-domain and 5 out-of-domain tasks demonstrate that GeLLM^3Os consistently outperform state-of-the-art baselines. GeLLM^3Os also exhibit outstanding zero-shot generalization to unseen tasks, significantly outperforming powerful closed-source LLMs. Such strong generalizability demonstrates the tremendous potential of GeLLM^3Os as foundational models for molecule optimization, thereby tackling novel optimization tasks without resource-intensive retraining. MoMUInstruct, models, and code are accessible through https://github.com/ninglab/GeLLMO.

Antibodies have become an important class of therapeutic agents to treat human diseases. To accelerate therapeutic antibody discovery, computational methods, especially machine learning, have attracted considerable interest for predicting specific interactions between antibody candidates and target antigens such as viruses and bacteria. However, the publicly available datasets in existing works have notable limitations, such as small sizes and the lack of non-binding samples and exact amino acid sequences. To overcome these limitations, we have developed AVIDa-hIL6, a large-scale dataset for predicting antigen-antibody interactions in the variable domain of heavy chain of heavy chain antibodies (VHHs), produced from an alpaca immunized with the human interleukin-6 (IL-6) protein, as antigens. By leveraging the simple structure of VHHs, which facilitates identification of full-length amino acid sequences by DNA sequencing technology, AVIDa-hIL6 contains 573,891 antigen-VHH pairs with amino acid sequences. All the antigen-VHH pairs have reliable labels for binding or non-binding, as generated by a novel labeling method. Furthermore, via introduction of artificial mutations, AVIDa-hIL6 contains 30 different mutants in addition to wild-type IL-6 protein. This characteristic provides opportunities to develop machine learning models for predicting changes in antibody binding by antigen mutations. We report experimental benchmark results on AVIDa-hIL6 by using neural network-based baseline models. The results indicate that the existing models have potential, but further research is needed to generalize them to predict effective antibodies against unknown mutants. The dataset is available at https://avida-hil6.cognanous.com.

This paper introduces MM-Instruct, a large-scale dataset of diverse and high-quality visual instruction data designed to enhance the instruction-following capabilities of large multimodal models (LMMs). While existing visual instruction datasets often focus on question-answering, they struggle to generalize to broader application scenarios such as creative writing, summarization, or image analysis. To address these limitations, we propose a novel approach to constructing MM-Instruct that leverages the strong instruction-following capabilities of existing LLMs to generate novel visual instruction data from large-scale but conventional image captioning datasets. MM-Instruct first leverages ChatGPT to automatically generate diverse instructions from a small set of seed instructions through augmenting and summarization. It then matches these instructions with images and uses an open-sourced large language model (LLM) to generate coherent answers to the instruction-image pairs. The LLM is grounded by the detailed text descriptions of images in the whole answer generation process to guarantee the alignment of the instruction data. Moreover, we introduce a benchmark based on the generated instruction data to evaluate the instruction-following capabilities of existing LMMs. We demonstrate the effectiveness of MM-Instruct by training a LLaVA-1.5 model on the generated data, denoted as LLaVA-Instruct, which exhibits significant improvements in instruction-following capabilities compared to LLaVA-1.5 models. The MM-Instruct dataset, benchmark, and pre-trained models are available at https://github.com/jihaonew/MM-Instruct.

Current multimodal language models (MLMs) evaluation and training approaches overlook the influence of instruction format, presenting an elephant-in-the-room problem. Previous research deals with this problem by manually crafting instructions, failing to yield significant insights due to limitations in diversity and scalability. In this work, we propose a programmatic instruction template generator capable of producing over 39B unique template combinations by filling randomly sampled positional synonyms into weighted sampled meta templates, enabling us to comprehensively examine the MLM's performance across diverse instruction templates. Our experiments across eight common MLMs on five benchmark datasets reveal that MLMs have high template sensitivities with at most 29% performance gaps between different templates. We further augment the instruction tuning dataset of LLaVA-1.5 with our template generator and perform instruction tuning on LLaVA-1.5-7B and LLaVA-1.5-13B. Models tuned on our augmented dataset achieve the best overall performance when compared with the same scale MLMs tuned on at most 75 times the scale of our augmented dataset, highlighting the importance of instruction templates in MLM training. The code is available at https://github.com/shijian2001/TemplateMatters .

Automatic generation of graphical layouts is crucial for many real-world applications, including designing posters, flyers, advertisements, and graphical user interfaces. Given the incredible ability of Large language models (LLMs) in both natural language understanding and generation, we believe that we could customize an LLM to help people create compelling graphical layouts starting with only text instructions from the user. We call our method TextLap (text-based layout planning). It uses a curated instruction-based layout planning dataset (InsLap) to customize LLMs as a graphic designer. We demonstrate the effectiveness of TextLap and show that it outperforms strong baselines, including GPT-4 based methods, for image generation and graphical design benchmarks.