Humans and language models diverge when predicting repeating text

Abstract: Language models that are trained on the next-word prediction task have been shown to accurately model human behavior in word prediction and reading speed. In contrast with these findings, we present a scenario in which the performance of humans and LMs diverges. We collected a dataset of human next-word predictions for five stimuli that are formed by repeating spans of text. Human and GPT-2 LM predictions are strongly aligned in the first presentation of a text span, but their performance quickly diverges when memory (or in-context learning) begins to play a role. We traced the cause of this divergence to specific attention heads in a middle layer. Adding a power-law recency bias to these attention heads yielded a model that performs much more similarly to humans. We hope that this scenario will spur future work in bringing LMs closer to human behavior.

Aditya R. Vaidya
Javier Turek
Alexander G. Huth


Growing ecosystem of deep learning methods for modeling protein$\unicode{x2013}$protein interactions

Abstract: Numerous cellular functions rely on protein$\unicode{x2013}$protein interactions. Efforts to comprehensively characterize them remain challenged however by the diversity of molecular recognition mechanisms employed within the proteome. Deep learning has emerged as a promising approach for tackling this problem by exploiting both experimental data and basic biophysical knowledge about protein interactions. Here, we review the growing ecosystem of deep learning methods for modeling protein interactions, highlighting the diversity of these biophysically-informed models and their respective trade-offs. We discuss recent successes in using representation learning to capture complex features pertinent to predicting protein interactions and interaction sites, geometric deep learning to reason over protein structures and predict complex structures, and generative modeling to design de novo protein assemblies. We also outline some of the outstanding challenges and promising new directions. Opportunities abound to discover novel interactions, elucidate their physical mechanisms, and engineer binders to modulate their functions using deep learning and, ultimately, unravel how protein interactions orchestrate complex cellular behaviors.

Julia R. Rogers
Gergő Nikolényi
Mohammed AlQuraishi


VQPL: Vector Quantized Protein Language

Abstract: Is there a foreign language describing protein sequences and structures simultaneously? Protein structures, represented by continuous 3D points, have long posed a challenge due to the contrasting modeling paradigms of discrete sequences. To represent protein sequence-structure as discrete symbols, we propose a VQProteinformer to project residue types and structures into a discrete space, supervised by a reconstruction loss to ensure information preservation. The sequential latent codes of residues introduce a new quantized protein language, transforming the protein sequence-structure into a unified modality. We demonstrate the potential of the created protein language on predictive and generative tasks, which may not only advance protein research but also establish a connection between the protein-related and NLP-related fields. The proposed method will be continually improved to unify more protein modalities, including text and point cloud.


PGraphDTA: Improving Drug Target Interaction Prediction using Protein Language Models and Contact Maps

Abstract: Developing and discovering new drugs is a complex and resource-intensive endeavor that often involves substantial costs, time investment, and safety concerns. A key aspect of drug discovery involves identifying novel drug-target (DT) interactions. Existing computational methods for predicting DT interactions have primarily focused on binary classification tasks, aiming to determine whether a DT pair interacts or not. However, protein-ligand interactions exhibit a continuum of binding strengths, known as binding affinity, presenting a persistent challenge for accurate prediction. In this study, we investigate various techniques employed in Drug Target Interaction (DTI) prediction and propose novel enhancements to enhance their performance. Our approaches include the integration of Protein Language Models (PLMs) and the incorporation of Contact Map information as an inductive bias within current models. Through extensive experimentation, we demonstrate that our proposed approaches outperform the baseline models considered in this study, presenting a compelling case for further development in this direction. We anticipate that the insights gained from this work will significantly narrow the search space for potential drugs targeting specific proteins, thereby accelerating drug discovery. Code and data for PGraphDTA are available at https://github.com/Yijia-Xiao/PgraphDTA/.


InstructProtein: Aligning Human and Protein Language via Knowledge Instruction

Abstract: 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.

Zeyuan Wang
Qiang Zhang
Keyan Ding
Ming Qin
Xiang Zhuang
Xiaotong Li
Huajun Chen

Annual Meeting of the Association for Computational Linguistics


CrysFormer: Protein Structure Prediction via 3d Patterson Maps and Partial Structure Attention

Abstract: Determining the structure of a protein has been a decades-long open question. A protein's three-dimensional structure often poses nontrivial computation costs, when classical simulation algorithms are utilized. Advances in the transformer neural network architecture -- such as AlphaFold2 -- achieve significant improvements for this problem, by learning from a large dataset of sequence information and corresponding protein structures. Yet, such methods only focus on sequence information; other available prior knowledge, such as protein crystallography and partial structure of amino acids, could be potentially utilized. To the best of our knowledge, we propose the first transformer-based model that directly utilizes protein crystallography and partial structure information to predict the electron density maps of proteins. Via two new datasets of peptide fragments (2-residue and 15-residue) , we demonstrate our method, dubbed \texttt{CrysFormer}, can achieve accurate predictions, based on a much smaller dataset size and with reduced computation costs.

Chen Dun
Qiutai Pan
Shikai Jin
Ria Stevens
Mitchell D. Miller
George N. Phillips,
Anastasios Kyrillidis


All Languages Matter: On the Multilingual Safety of Large Language Models

Abstract: Safety lies at the core of developing and deploying large language models (LLMs). However, previous safety benchmarks only concern the safety in one language, e.g. the majority language in the pretraining data such as English. In this work, we build the first multilingual safety benchmark for LLMs, XSafety, in response to the global deployment of LLMs in practice. XSafety covers 14 kinds of commonly used safety issues across 10 languages that span several language families. We utilize XSafety to empirically study the multilingual safety for 4 widely-used LLMs, including both close-API and open-source models. Experimental results show that all LLMs produce significantly more unsafe responses for non-English queries than English ones, indicating the necessity of developing safety alignment for non-English languages. In addition, we propose several simple and effective prompting methods to improve the multilingual safety of ChatGPT by evoking safety knowledge and improving cross-lingual generalization of safety alignment. Our prompting method can significantly reduce the ratio of unsafe responses from 19.1% to 9.7% for non-English queries. We release our data at https://github.com/Jarviswang94/Multilingual_safety_benchmark.

Wenxuan Wang
Zhaopeng Tu
Chang Chen
Youliang Yuan
Jen-tse Huang
Wenxiang Jiao
Michael R. Lyu


PB-LLM: Partially Binarized Large Language Models

Abstract: This paper explores network binarization, a radical form of quantization, compressing model weights to a single bit, specifically for Large Language Models (LLMs) compression. Due to previous binarization methods collapsing LLMs, we propose a novel approach, Partially-Binarized LLM (PB-LLM), which can achieve extreme low-bit quantization while maintaining the linguistic reasoning capacity of quantized LLMs. Specifically, our exploration first uncovers the ineffectiveness of naive applications of existing binarization algorithms and highlights the imperative role of salient weights in achieving low-bit quantization. Thus, PB-LLM filters a small ratio of salient weights during binarization, allocating them to higher-bit storage, i.e., partially-binarization. PB-LLM is extended to recover the capacities of quantized LMMs, by analyzing from the perspective of post-training quantization (PTQ) and quantization-aware training (QAT). Under PTQ, combining the concepts from GPTQ, we reconstruct the binarized weight matrix guided by the Hessian matrix and successfully recover the reasoning capacity of PB-LLM in low-bit. Under QAT, we freeze the salient weights during training, explore the derivation of optimal scaling factors crucial for minimizing the quantization error, and propose a scaling mechanism based on this derived scaling strategy for residual binarized weights. Those explorations and the developed methodologies significantly contribute to rejuvenating the performance of low-bit quantized LLMs and present substantial advancements in the field of network binarization for LLMs.The code is available at https://github.com/hahnyuan/BinaryLLM.

Yuzhang Shang
Zhihang Yuan
Qiang Wu
Zhen Dong

International Conference on Learning Representations


pLMFPPred: a novel approach for accurate prediction of functional peptides integrating embedding from pre-trained protein language model and imbalanced learning

Abstract: Functional peptides have the potential to treat a variety of diseases. Their good therapeutic efficacy and low toxicity make them ideal therapeutic agents. Artificial intelligence-based computational strategies can help quickly identify new functional peptides from collections of protein sequences and discover their different functions.Using protein language model-based embeddings (ESM-2), we developed a tool called pLMFPPred (Protein Language Model-based Functional Peptide Predictor) for predicting functional peptides and identifying toxic peptides. We also introduced SMOTE-TOMEK data synthesis sampling and Shapley value-based feature selection techniques to relieve data imbalance issues and reduce computational costs. On a validated independent test set, pLMFPPred achieved accuracy, Area under the curve - Receiver Operating Characteristics, and F1-Score values of 0.974, 0.99, and 0.974, respectively. Comparative experiments show that pLMFPPred outperforms current methods for predicting functional peptides.The experimental results suggest that the proposed method (pLMFPPred) can provide better performance in terms of Accuracy, Area under the curve - Receiver Operating Characteristics, and F1-Score than existing methods. pLMFPPred has achieved good performance in predicting functional peptides and represents a new computational method for predicting functional peptides.

Zebin Ma
Yonglin Zou
Xiaobin Huang
Wenjin Yan
Hao Xu
Jiexin Yang
Ying Zhang
Jinqi Huang


Speaker attribution in German parliamentary debates with QLoRA-adapted large language models

Abstract: The growing body of political texts opens up new opportunities for rich insights into political dynamics and ideologies but also increases the workload for manual analysis. Automated speaker attribution, which detects who said what to whom in a speech event and is closely related to semantic role labeling, is an important processing step for computational text analysis. We study the potential of the large language model family Llama 2 to automate speaker attribution in German parliamentary debates from 2017-2021. We fine-tune Llama 2 with QLoRA, an efficient training strategy, and observe our approach to achieve competitive performance in the GermEval 2023 Shared Task On Speaker Attribution in German News Articles and Parliamentary Debates. Our results shed light on the capabilities of large language models in automating speaker attribution, revealing a promising avenue for computational analysis of political discourse and the development of semantic role labeling systems.

Tobias Bornheim
Niklas Grieger
Patrick Gustav Blaneck
Stephan Bialonski

Journal for Language Technology and Computational Linguistics


Jais and Jais-chat: Arabic-Centric Foundation and Instruction-Tuned Open Generative Large Language Models

Abstract: We introduce Jais and Jais-chat, new state-of-the-art Arabic-centric foundation and instruction-tuned open generative large language models (LLMs). The models are based on the GPT-3 decoder-only architecture and are pretrained on a mixture of Arabic and English texts, including source code in various programming languages. With 13 billion parameters, they demonstrate better knowledge and reasoning capabilities in Arabic than any existing open Arabic and multilingual models by a sizable margin, based on extensive evaluation. Moreover, the models are competitive in English compared to English-centric open models of similar size, despite being trained on much less English data. We provide a detailed description of the training, the tuning, the safety alignment, and the evaluation of the models. We release two open versions of the model -- the foundation Jais model, and an instruction-tuned Jais-chat variant -- with the aim of promoting research on Arabic LLMs. Available at https://huggingface.co/inception-mbzuai/jais-13b-chat

Neha Sengupta
Sunil Kumar Sahu
Bokang Jia
Satheesh Katipomu
Haonan Li
Fajri Koto
William Marshall
Gurpreet Gosal
Cynthia Liu
Zhiming Chen
Osama Mohammed Afzal
Samta Kamboj
Onkar Pandit
Rahul Pal
Lalit Pradhan
Zain Muhammad Mujahid
Massa Baali
Xudong Han
Sondos Mahmoud Bsharat
Alham Fikri Aji
Zhiqiang Shen
Zhengzhong Liu
Natalia Vassilieva
Joel Hestness
Andy Hock
Andrew Feldman
Jonathan Lee
Andrew Jackson
Hector Xuguang Ren
Preslav Nakov
Timothy Baldwin
Eric Xing


Atom-by-atom protein generation and beyond with language models

Abstract: Protein language models learn powerful representations directly from sequences of amino acids. However, they are constrained to generate proteins with only the set of amino acids represented in their vocabulary. In contrast, chemical language models learn atom-level representations of smaller molecules that include every atom, bond, and ring. In this work, we show that chemical language models can learn atom-level representations of proteins enabling protein generation unconstrained to the standard genetic code and far beyond it. In doing so, we show that language models can generate entire proteins atom by atom -- effectively learning the multiple hierarchical layers of molecular information that define proteins from their primary sequence to their secondary, and tertiary structure. We demonstrate language models are able to explore beyond protein space -- generating proteins with modified sidechains that form unnatural amino acids. Even further, we find that language models can explore chemical space and protein space simultaneously and generate novel examples of protein-drug conjugates. The results demonstrate the potential for biomolecular design at the atom level using language models.

Daniel Flam-Shepherd
Kevin Zhu
Alán Aspuru-Guzik


PEvoLM: Protein Sequence Evolutionary Information Language Model

Abstract: With the exponential increase of the protein sequence databases over time, multiple-sequence alignment (MSA) methods, like PSI-BLAST, perform exhaustive and time-consuming database search to retrieve evolutionary information. The resulting position-specific scoring matrices (PSSMs) of such search engines represent a crucial input to many machine learning (ML) models in the field of bioinformatics and computational biology. A protein sequence is a collection of contiguous tokens or characters called amino acids (AAs). The analogy to natural language allowed us to exploit the recent advancements in the field of Natural Language Processing (NLP) and therefore transfer NLP state-of-the-art algorithms to bioinformatics. This research presents an Embedding Language Model (ELMo), converting a protein sequence to a numerical vector representation. While the original ELMo trained a 2-layer bidirectional Long Short-Term Memory (LSTMs) network following a two-path architecture, one for the forward and the second for the backward pass, by merging the idea of PSSMs with the concept of transfer-learning, this work introduces a novel bidirectional language model (bi-LM) with four times less free parameters and using rather a single path for both passes. The model was trained not only on predicting the next AA but also on the probability distribution of the next AA derived from similar, yet different sequences as summarized in a PSSM, simultaneously for multi-task learning, hence learning evolutionary information of protein sequences as well. The network architecture and the pre-trained model are made available as open source under the permissive MIT license on GitHub at https://github.com/issararab/PEvoLM.

IEEE Symposium on Computational Intelligence in Bioinformatics and Computational Biology


Pairing interacting protein sequences using masked language modeling

Abstract: 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.

Umberto Lupo
Damiano Sgarbossa
Anne-Florence Bitbol


FFF: Fragments-Guided Flexible Fitting for Building Complete Protein Structures

Abstract: 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.


Turkish Native Language Identification V2

Abstract: This paper presents the first application of Native Language Identification (NLI) for the Turkish language. NLI is the task of automatically identifying an individual's native language (L1) based on their writing or speech in a non-native language (L2). While most NLI research has focused on L2 English, our study extends this scope to L2 Turkish by analyzing a corpus of texts written by native speakers of Albanian, Arabic and Persian. We leverage a cleaned version of the Turkish Learner Corpus and demonstrate the effectiveness of syntactic features, comparing a structural Part-of-Speech n-gram model to a hybrid model that retains function words. Our models achieve promising results, and we analyze the most predictive features to reveal L1-specific transfer effects. We make our data and code publicly available for further study.

International Conference on Natural Language and Speech Processing


Artificial intelligence-aided protein engineering: from topological data analysis to deep protein language models

Abstract: Protein engineering is an emerging field in biotechnology that has the potential to revolutionize various areas, such as antibody design, drug discovery, food security, ecology, and more. However, the mutational space involved is too vast to be handled through experimental means alone. Leveraging accumulative protein databases, machine learning (ML) models, particularly those based on natural language processing (NLP), have considerably expedited protein engineering. Moreover, advances in topological data analysis (TDA) and artificial intelligence-based protein structure prediction, such as AlphaFold2, have made more powerful structure-based ML-assisted protein engineering strategies possible. This review aims to offer a comprehensive, systematic, and indispensable set of methodological components, including TDA and NLP, for protein engineering and to facilitate their future development.


Predicting Relative Populations of Protein Conformations without a Physics Engine Using AlphaFold2

Abstract: This paper presents a novel approach for predicting the relative populations of protein conformations using AlphaFold 2, an AI-powered method that has revolutionized biology by enabling the accurate prediction of protein structures. While AlphaFold 2 has shown exceptional accuracy and speed, it is designed to predict proteins' single ground state conformations and is limited in its ability to predict fold switching and the effects of mutations on conformational landscapes. Here, we demonstrate how AlphaFold 2 can directly predict the relative populations of different conformations of proteins and even accurately predict changes in those populations induced by mutations by subsampling multiple sequence alignments. We tested our method against NMR experiments on two proteins with drastically different amounts of available sequence data, Abl1 kinase and the granulocyte-macrophage colony-stimulating factor, and predicted changes in their relative state populations with accuracies in excess of 80%. Our method offers a fast and cost-effective way to predict protein conformations and their relative populations at even single point mutation resolution, making it a useful tool for pharmacology, analyzing NMR data, and studying the effects of evolution.

Gabriel Monteiro da Silva
Jennifer Y. Cui
David C. Dalgarno
George P. Lisi
Brenda M. Rubenstein


DeepGATGO: A Hierarchical Pretraining-Based Graph-Attention Model for Automatic Protein Function Prediction

Abstract: Automatic protein function prediction (AFP) is classified as a large-scale multi-label classification problem aimed at automating protein enrichment analysis to eliminate the current reliance on labor-intensive wet-lab methods. Currently, popular methods primarily combine protein-related information and Gene Ontology (GO) terms to generate final functional predictions. For example, protein sequences, structural information, and protein-protein interaction networks are integrated as prior knowledge to fuse with GO term embeddings and generate the ultimate prediction results. However, these methods are limited by the difficulty in obtaining structural information or network topology information, as well as the accuracy of such data. Therefore, more and more methods that only use protein sequences for protein function prediction have been proposed, which is a more reliable and computationally cheaper approach. However, the existing methods fail to fully extract feature information from protein sequences or label data because they do not adequately consider the intrinsic characteristics of the data itself. Therefore, we propose a sequence-based hierarchical prediction method, DeepGATGO, which processes protein sequences and GO term labels hierarchically, and utilizes graph attention networks (GATs) and contrastive learning for protein function prediction. Specifically, we compute embeddings of the sequence and label data using pre-trained models to reduce computational costs and improve the embedding accuracy. Then, we use GATs to dynamically extract the structural information of non-Euclidean data, and learn general features of the label dataset with contrastive learning by constructing positive and negative example samples. Experimental results demonstrate that our proposed model exhibits better scalability in GO term enrichment analysis on large-scale datasets.


A Zero-shot and Few-shot Study of Instruction-Finetuned Large Language Models Applied to Clinical and Biomedical Tasks

Abstract: We evaluate four state-of-the-art instruction-tuned large language models (LLMs) -- ChatGPT, Flan-T5 UL2, Tk-Instruct, and Alpaca -- on a set of 13 real-world clinical and biomedical natural language processing (NLP) tasks in English, such as named-entity recognition (NER), question-answering (QA), relation extraction (RE), etc. Our overall results demonstrate that the evaluated LLMs begin to approach performance of state-of-the-art models in zero- and few-shot scenarios for most tasks, and particularly well for the QA task, even though they have never seen examples from these tasks before. However, we observed that the classification and RE tasks perform below what can be achieved with a specifically trained model for the medical field, such as PubMedBERT. Finally, we noted that no LLM outperforms all the others on all the studied tasks, with some models being better suited for certain tasks than others.

Yanis Labrak
Mickael Rouvier
Richard Dufour

International Conference on Language Resources and Evaluation


Introduction to Protein Structure

Abstract: While many good textbooks are available on Protein Structure, Molecular Simulations, Thermodynamics and Bioinformatics methods in general, there is no good introductory level book for the field of Structural Bioinformatics. This book aims to give an introduction into Structural Bioinformatics, which is where the previous topics meet to explore three dimensional protein structures through computational analysis. We provide an overview of existing computational techniques, to validate, simulate, predict and analyse protein structures. More importantly, it will aim to provide practical knowledge about how and when to use such techniques. We will consider proteins from three major vantage points: Protein structure quantification, Protein structure prediction, and Protein simulation & dynamics. Within the living cell, protein molecules perform specific functions, typically by interacting with other proteins, DNA, RNA or small molecules. They take on a specific three dimensional structure, encoded by its amino acid sequence, which allows them to function within the cell. Hence, the understanding of a protein's function is tightly coupled to its sequence and its three dimensional structure. Before going into protein structure analysis and prediction, and protein folding and dynamics, here, we give a short and concise introduction into the basics of protein structures.

Annika Jacobsen
Erik van Dijk
Halima Mouhib
Bas Stringer
Olga Ivanova
Jose Gavaldá-Garciá
Laura Hoekstra
K. Anton Feenstra
Sanne Abeln


Monte Carlo for Protein Structures

Abstract: While many good textbooks are available on Protein Structure, Molecular Simulations, Thermodynamics and Bioinformatics methods in general, there is no good introductory level book for the field of Structural Bioinformatics. This book aims to give an introduction into Structural Bioinformatics, which is where the previous topics meet to explore three dimensional protein structures through computational analysis. We provide an overview of existing computational techniques, to validate, simulate, predict and analyse protein structures. More importantly, it will aim to provide practical knowledge about how and when to use such techniques. We will consider proteins from three major vantage points: Protein structure quantification, Protein structure prediction, and Protein simulation & dynamics. In the previous chapter "Molecular Dynamics" we have considered protein simulations from a dynamical point of view, using Newton's laws. In the current Chapter, we first take a step back and return to the bare minimum needed to simulate proteins, and show that proteins may be simulated in a more simple fashion, using the partition function directly. This means we do not have to calculate explicit forces, velocities, moments and do not even consider time explicitly. Instead, we will rely on the fact that for most systems we will want to simulate, the system is in a dynamic equilibrium; and that we want to find the most stable states in such systems by determining the relative stabilities between those states.

Juami H. M. van Gils
Maurits Dijkstra
Halima Mouhib
Arriën Symon Rauh
Jocelyne Vreede
K. Anton Feenstra
Sanne Abeln


Introduction to Protein Folding

Abstract: While many good textbooks are available on Protein Structure, Molecular Simulations, Thermodynamics and Bioinformatics methods in general, there is no good introductory level book for the field of Structural Bioinformatics. This book aims to give an introduction into Structural Bioinformatics, which is where the previous topics meet to explore three dimensional protein structures through computational analysis. We provide an overview of existing computational techniques, to validate, simulate, predict and analyse protein structures. More importantly, it will aim to provide practical knowledge about how and when to use such techniques. We will consider proteins from three major vantage points: Protein structure quantification, Protein structure prediction, and Protein simulation & dynamics. In this chapter we explore basic physical and chemical concepts required to understand protein folding. We introduce major (de)stabilising factors of folded protein structures such as the hydrophobic effect and backbone entropy. In addition, we consider different states along the folding pathway, as well as natively disordered proteins and aggregated protein states. In this chapter, an intuitive understanding is provided about the protein folding process, to prepare for the next chapter on the thermodynamics of protein folding. In particular, it is emphasized that protein folding is a stochastic process and that proteins unfold and refold in a dynamic equilibrium. The effect of temperature on the stability of the folded and unfolded states is also explained.

Juami H. M. van Gils
Erik van Dijk
Ali May
Halima Mouhib
Jochem Bijlard
Annika Jacobsen
Isabel Houtkamp
K. Anton Feenstra
Sanne Abeln


Thermodynamics of Protein Folding

Abstract: While many good textbooks are available on Protein Structure, Molecular Simulations, Thermodynamics and Bioinformatics methods in general, there is no good introductory level book for the field of Structural Bioinformatics. This book aims to give an introduction into Structural Bioinformatics, which is where the previous topics meet to explore three dimensional protein structures through computational analysis. We provide an overview of existing computational techniques, to validate, simulate, predict and analyse protein structures. More importantly, it will aim to provide practical knowledge about how and when to use such techniques. We will consider proteins from three major vantage points: Protein structure quantification, Protein structure prediction, and Protein simulation & dynamics. In the previous chapter, "Introduction to Protein Folding", we introduced the concept of free energy and the protein folding landscape. Here, we provide a deeper, more formal underpinning of free energy in terms of the entropy and enthalpy; to this end, we will first need to better define the meaning of equilibrium, entropy and enthalpy. When we understand these concepts, we will come back for a more quantitative explanation of protein folding and dynamics. We will discuss the influence of temperature on the free energy landscape, and the difference between microstates and macrostates.

Juami H. M. van Gils
Halima Mouhib
Erik van Dijk
Maurits Dijkstra
Isabel Houtkamp
Arthur Goetzee
Sanne Abeln
K. Anton Feenstra


Structural Property Prediction

Abstract: While many good textbooks are available on Protein Structure, Molecular Simulations, Thermodynamics and Bioinformatics methods in general, there is no good introductory level book for the field of Structural Bioinformatics. This book aims to give an introduction into Structural Bioinformatics, which is where the previous topics meet to explore three dimensional protein structures through computational analysis. We provide an overview of existing computational techniques, to validate, simulate, predict and analyse protein structures. More importantly, it will aim to provide practical knowledge about how and when to use such techniques. We will consider proteins from three major vantage points: Protein structure quantification, Protein structure prediction, and Protein simulation & dynamics. Some structural properties of proteins that are closely linked to their function may be easier (or much faster) to predict from sequence than the complete tertiary structure; for example, secondary structure, surface accessibility, flexibility, disorder, interface regions or hydrophobic patches. Serving as building blocks for the native protein fold, these structural properties also contain important structural and functional information not apparent from the amino acid sequence. Here, we will first give an introduction into the application of machine learning for structural property prediction, and explain the concepts of cross-validation and benchmarking. Next, we will review various methods that incorporate knowledge of these concepts to predict those structural properties, such as secondary structure, surface accessibility, disorder and flexibility, and aggregation.

Maurits Dijkstra
Punto Bawono
Isabel Houtkamp
Jose Gavaldá-Garciá
Mascha Okounev
Robbin Bouwmeester
Bas Stringer
Jaap Heringa
Sanne Abeln
K. Anton Feenstra
Juami H. M. van Gils


ALBERTI, a Multilingual Domain Specific Language Model for Poetry Analysis

Abstract: The computational analysis of poetry is limited by the scarcity of tools to automatically analyze and scan poems. In a multilingual settings, the problem is exacerbated as scansion and rhyme systems only exist for individual languages, making comparative studies very challenging and time consuming. In this work, we present \textsc{Alberti}, the first multilingual pre-trained large language model for poetry. Through domain-specific pre-training (DSP), we further trained multilingual BERT on a corpus of over 12 million verses from 12 languages. We evaluated its performance on two structural poetry tasks: Spanish stanza type classification, and metrical pattern prediction for Spanish, English and German. In both cases, \textsc{Alberti} outperforms multilingual BERT and other transformers-based models of similar sizes, and even achieves state-of-the-art results for German when compared to rule-based systems, demonstrating the feasibility and effectiveness of DSP in the poetry domain.

Javier de la Rosa
Álvaro Pérez Pozo
Salvador Ros
Elena González-Blanco


Protein-DNA binding sites prediction based on pre-trained protein language model and contrastive learning

Abstract: Protein-DNA interaction is critical for life activities such as replication, transcription, and splicing. Identifying protein-DNA binding residues is essential for modeling their interaction and downstream studies. However, developing accurate and efficient computational methods for this task remains challenging. Improvements in this area have the potential to drive novel applications in biotechnology and drug design. In this study, we propose a novel approach called CLAPE, which combines a pre-trained protein language model and the contrastive learning method to predict DNA binding residues. We trained the CLAPE-DB model on the protein-DNA binding sites dataset and evaluated the model performance and generalization ability through various experiments. The results showed that the AUC values of the CLAPE-DB model on the two benchmark datasets reached 0.871 and 0.881, respectively, indicating superior performance compared to other existing models. CLAPE-DB showed better generalization ability and was specific to DNA-binding sites. In addition, we trained CLAPE on different protein-ligand binding sites datasets, demonstrating that CLAPE is a general framework for binding sites prediction. To facilitate the scientific community, the benchmark datasets and codes are freely available at https://github.com/YAndrewL/clape.


WizardCoder: Empowering Code Large Language Models with Evol-Instruct

Abstract: Code Large Language Models (Code LLMs), such as StarCoder, have demonstrated exceptional performance in code-related tasks. However, most existing models are solely pre-trained on extensive raw code data without instruction fine-tuning. In this paper, we introduce WizardCoder, which empowers Code LLMs with complex instruction fine-tuning, by adapting the Evol-Instruct method to the domain of code. Through comprehensive experiments on four prominent code generation benchmarks, namely HumanEval, HumanEval+, MBPP, and DS-1000, we unveil the exceptional capabilities of our model. It surpasses all other open-source Code LLMs by a substantial margin. Moreover, our model even outperforms the largest closed LLMs, Anthropic's Claude and Google's Bard, on HumanEval and HumanEval+. Our code, model weights, and data are public at https://github.com/nlpxucan/WizardLM

Ziyang Luo
Can Xu
Pu Zhao
Qingfeng Sun
Xiubo Geng
Wenxiang Hu
Chongyang Tao
Jing Ma
Qingwei Lin
Daxin Jiang


A Comprehensive Review of State-of-The-Art Methods for Java Code Generation from Natural Language Text

Abstract: Java Code Generation consists in generating automatically Java code from a Natural Language Text. This NLP task helps in increasing programmers' productivity by providing them with immediate solutions to the simplest and most repetitive tasks. Code generation is a challenging task because of the hard syntactic rules and the necessity of a deep understanding of the semantic aspect of the programming language. Many works tried to tackle this task using either RNN-based, or Transformer-based models. The latter achieved remarkable advancement in the domain and they can be divided into three groups: (1) encoder-only models, (2) decoder-only models, and (3) encoder-decoder models. In this paper, we provide a comprehensive review of the evolution and progress of deep learning models in Java code generation task. We focus on the most important methods and present their merits and limitations, as well as the objective functions used by the community. In addition, we provide a detailed description of datasets and evaluation metrics used in the literature. Finally, we discuss results of different models on CONCODE dataset, then propose some future directions.

Jessica López Espejel
Mahaman Sanoussi Yahaya Alassan
El Mehdi Chouham
Walid Dahhane
El Hassane Ettifouri


Multi-level Protein Representation Learning for Blind Mutational Effect Prediction

Abstract: Directed evolution plays an indispensable role in protein engineering that revises existing protein sequences to attain new or enhanced functions. Accurately predicting the effects of protein variants necessitates an in-depth understanding of protein structure and function. Although large self-supervised language models have demonstrated remarkable performance in zero-shot inference using only protein sequences, these models inherently do not interpret the spatial characteristics of protein structures, which are crucial for comprehending protein folding stability and internal molecular interactions. This paper introduces a novel pre-training framework that cascades sequential and geometric analyzers for protein primary and tertiary structures. It guides mutational directions toward desired traits by simulating natural selection on wild-type proteins and evaluates the effects of variants based on their fitness to perform the function. We assess the proposed approach using a public database and two new databases for a variety of variant effect prediction tasks, which encompass a diverse set of proteins and assays from different taxa. The prediction results achieve state-of-the-art performance over other zero-shot learning methods for both single-site mutations and deep mutations.

Yang Tan
Bingxin Zhou
Yuanhong Jiang
Yu Guang Wang
Liang Hong


Enhancing the Protein Tertiary Structure Prediction by Multiple Sequence Alignment Generation

Abstract: The field of protein folding research has been greatly advanced by deep learning methods, with AlphaFold2 (AF2) demonstrating exceptional performance and atomic-level precision. As co-evolution is integral to protein structure prediction, AF2's accuracy is significantly influenced by the depth of multiple sequence alignment (MSA), which requires extensive exploration of a large protein database for similar sequences. However, not all protein sequences possess abundant homologous families, and consequently, AF2's performance can degrade on such queries, at times failing to produce meaningful results. To address this, we introduce a novel generative language model, MSA-Augmenter, which leverages protein-specific attention mechanisms and large-scale MSAs to generate useful, novel protein sequences not currently found in databases. These sequences supplement shallow MSAs, enhancing the accuracy of structural property predictions. Our experiments on CASP14 demonstrate that MSA-Augmenter can generate de novo sequences that retain co-evolutionary information from inferior MSAs, thereby improving protein structure prediction quality on top of strong AF2.

Le Zhang
Jiayang Chen
Tao Shen
Yu Li
Siqi Sun


AF2-Mutation: Adversarial Sequence Mutations against AlphaFold2 on Protein Tertiary Structure Prediction

Abstract: Deep learning-based approaches, such as AlphaFold2 (AF2), have significantly advanced protein tertiary structure prediction, achieving results comparable to real biological experimental methods. While AF2 has shown limitations in predicting the effects of mutations, its robustness against sequence mutations remains to be determined. Starting with the wild-type (WT) sequence, we investigate adversarial sequences generated via an evolutionary approach, which AF2 predicts to be substantially different from WT. Our experiments on CASP14 reveal that by modifying merely three residues in the protein sequence using a combination of replacement, deletion, and insertion strategies, the alteration in AF2's predictions, as measured by the Local Distance Difference Test (lDDT), reaches 46.61. Moreover, when applied to a specific protein, SPNS2, our proposed algorithm successfully identifies biologically meaningful residues critical to protein structure determination and potentially indicates alternative conformations, thus significantly expediting the experimental process.

Zhongju Yuan
Tao Shen
Sheng Xu
Leiye Yu
Ruobing Ren
Siqi Sun


A Latent Diffusion Model for Protein Structure Generation

Abstract: Proteins are complex biomolecules that perform a variety of crucial functions within living organisms. Designing and generating novel proteins can pave the way for many future synthetic biology applications, including drug discovery. However, it remains a challenging computational task due to the large modeling space of protein structures. In this study, we propose a latent diffusion model that can reduce the complexity of protein modeling while flexibly capturing the distribution of natural protein structures in a condensed latent space. Specifically, we propose an equivariant protein autoencoder that embeds proteins into a latent space and then uses an equivariant diffusion model to learn the distribution of the latent protein representations. Experimental results demonstrate that our method can effectively generate novel protein backbone structures with high designability and efficiency. The code will be made publicly available at https://github.com/divelab/AIRS/tree/main/OpenProt/LatentDiff

Cong Fu
Keqiang Yan
Limei Wang
Wing Yee Au
Michael McThrow
Tao Komikado
Koji Maruhashi
Kanji Uchino
Xiaoning Qian
Shuiwang Ji


WizardLM: Empowering large pre-trained language models to follow complex instructions

Abstract: Training large language models (LLMs) 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 and Vicuna's testset 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 are preferred to outputs from OpenAI ChatGPT. In GPT-4 automatic evaluation, WizardLM achieves more than 90\% capacity of ChatGPT on 17 out of 29 skills. 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 LLMs. Our code and data are public at https://github.com/nlpxucan/WizardLM

Can Xu
Qingfeng Sun
Kai Zheng
Xiubo Geng
Pu Zhao
Jiazhan Feng
Chongyang Tao
Qingwei Lin
Daxin Jiang


Learning to Plan with Natural Language

Abstract: Large Language Models (LLMs) have shown remarkable performance in various basic natural language tasks. For completing the complex task, we still need a plan for the task to guide LLMs to generate the specific solutions step by step. LLMs can directly generate task plans, but these plans may still contain factual errors or are incomplete. A high-quality task plan contains correct step-by-step solutions for solving all situations and behavioral instructions for avoiding mistakes. To obtain it, we propose the Learning to Plan method, which involves two phases: (1) In the first learning task plan phase, it iteratively updates the task plan with new step-by-step solutions and behavioral instructions, which are obtained by prompting LLMs to derive from training error feedback. (2) In the subsequent test phase, the LLM uses the learned task plan to guide the inference of LLM on the test set. We demonstrate the effectiveness of our method on the five different reasoning type tasks (8 datasets). Further, our analysis experiment shows that the task plan learned by one LLM can directly guide another LLM to improve its performance, which reveals a new transfer learning paradigm. We release the code at \url{https://github.com/Eureka6174/LearnNLPlan}

Yiduo Guo
Yaobo Liang
Chenfei Wu
Wenshan Wu
Dongyan Zhao
Nan Duan

Conference on Empirical Methods in Natural Language Processing


CodeKGC: Code Language Model for Generative Knowledge Graph Construction

Abstract: Current generative knowledge graph construction approaches usually fail to capture structural knowledge by simply flattening natural language into serialized texts or a specification language. However, large generative language model trained on structured data such as code has demonstrated impressive capability in understanding natural language for structural prediction and reasoning tasks. Intuitively, we address the task of generative knowledge graph construction with code language model: given a code-format natural language input, the target is to generate triples which can be represented as code completion tasks. Specifically, we develop schema-aware prompts that effectively utilize the semantic structure within the knowledge graph. As code inherently possesses structure, such as class and function definitions, it serves as a useful model for prior semantic structural knowledge. Furthermore, we employ a rationale-enhanced generation method to boost the performance. Rationales provide intermediate steps, thereby improving knowledge extraction abilities. Experimental results indicate that the proposed approach can obtain better performance on benchmark datasets compared with baselines. Code and datasets are available in https://github.com/zjunlp/DeepKE/tree/main/example/llm.

Zhen Bi
Jing Chen
Yinuo Jiang
Feiyu Xiong
Wei Guo
Huajun Chen
Ningyu Zhang


TemPL: A Novel Deep Learning Model for Zero-Shot Prediction of Protein Stability and Activity Based on Temperature-Guided Language Modeling

Abstract: We introduce TemPL, a novel deep learning approach for zero-shot prediction of protein stability and activity, harnessing temperature-guided language modeling. By assembling an extensive dataset of 96 million sequence-host bacterial strain optimal growth temperatures (OGTs) and ΔTm data for point mutations under consistent experimental conditions, we effectively compared TemPL with state-of-the-art models. Notably, TemPL demonstrated superior performance in predicting protein stability. An ablation study was conducted to elucidate the influence of OGT prediction and language modeling modules on TemPL's performance, revealing the importance of integrating both components. Consequently, TemPL offers considerable promise for protein engineering applications, facilitating the design of mutation sequences with enhanced stability and activity.

Pan Tan
Mingchen Li
Liang Zhang
Zhiqiang Hu
Liang Hong


EigenFold: Generative Protein Structure Prediction with Diffusion Models

Abstract: Protein structure prediction has reached revolutionary levels of accuracy on single structures, yet distributional modeling paradigms are needed to capture the conformational ensembles and flexibility that underlie biological function. Towards this goal, we develop EigenFold, a diffusion generative modeling framework for sampling a distribution of structures from a given protein sequence. We define a diffusion process that models the structure as a system of harmonic oscillators and which naturally induces a cascading-resolution generative process along the eigenmodes of the system. On recent CAMEO targets, EigenFold achieves a median TMScore of 0.84, while providing a more comprehensive picture of model uncertainty via the ensemble of sampled structures relative to existing methods. We then assess EigenFold's ability to model and predict conformational heterogeneity for fold-switching proteins and ligand-induced conformational change. Code is available at https://github.com/bjing2016/EigenFold.

Bowen Jing
Ezra Erives
Peter Pao-Huang
Gabriele Corso
Bonnie Berger
Tommi Jaakkola

Medicine
Computer Science
Biology
Physics


ProtFIM: Fill-in-Middle Protein Sequence Design via Protein Language Models

Abstract: Protein language models (pLMs), pre-trained via causal language modeling on protein sequences, have been a promising tool for protein sequence design. In real-world protein engineering, there are many cases where the amino acids in the middle of a protein sequence are optimized while maintaining other residues. Unfortunately, because of the left-to-right nature of pLMs, existing pLMs modify suffix residues by prompting prefix residues, which are insufficient for the infilling task that considers the whole surrounding context. To find the more effective pLMs for protein engineering, we design a new benchmark, Secondary structureE InFilling rEcoveRy, SEIFER, which approximates infilling sequence design scenarios. With the evaluation of existing models on the benchmark, we reveal the weakness of existing language models and show that language models trained via fill-in-middle transformation, called ProtFIM, are more appropriate for protein engineering. Also, we prove that ProtFIM generates protein sequences with decent protein representations through exhaustive experiments and visualizations.


A Systematic Study of Joint Representation Learning on Protein Sequences and Structures

Abstract: 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.

Zuobai Zhang
Chuanrui Wang
Minghao Xu
Vijil Chenthamarakshan
Aurélie Lozano
Payel Das
Jian Tang


Internal-Coordinate Density Modelling of Protein Structure: Covariance Matters

Abstract: After the recent ground-breaking advances in protein structure prediction, one of the remaining challenges in protein machine learning is to reliably predict distributions of structural states. Parametric models of fluctuations are difficult to fit due to complex covariance structures between degrees of freedom in the protein chain, often causing models to either violate local or global structural constraints. In this paper, we present a new strategy for modelling protein densities in internal coordinates, which uses constraints in 3D space to induce covariance structure between the internal degrees of freedom. We illustrate the potential of the procedure by constructing a variational autoencoder with full covariance output induced by the constraints implied by the conditional mean in 3D, and demonstrate that our approach makes it possible to scale density models of internal coordinates to full protein backbones in two settings: 1) a unimodal setting for proteins exhibiting small fluctuations and limited amounts of available data, and 2) a multimodal setting for larger conformational changes in a high data regime.

Marloes Arts
Jes Frellsen
Wouter Boomsma


Retrieved Sequence Augmentation for Protein Representation Learning

Abstract: Protein language models have excelled in a variety of tasks, ranging from structure prediction to protein engineering. However, proteins are highly diverse in functions and structures, and current state-of-the-art models including the latest version of AlphaFold rely on Multiple Sequence Alignments (MSA) to feed in the evolutionary knowledge. Despite their success, heavy computational overheads, as well as the de novo and orphan proteins remain great challenges in protein representation learning. In this work, we show that MSAaugmented models inherently belong to retrievalaugmented methods. Motivated by this finding, we introduce Retrieved Sequence Augmentation(RSA) for protein representation learning without additional alignment or pre-processing. RSA links query protein sequences to a set of sequences with similar structures or properties in the database and combines these sequences for downstream prediction. We show that protein language models benefit from the retrieval enhancement on both structure prediction and property prediction tasks, with a 5% improvement on MSA Transformer on average while being 373 times faster. In addition, we show that our model can transfer to new protein domains better and outperforms MSA Transformer on de novo protein prediction. Our study fills a much-encountered gap in protein prediction and brings us a step closer to demystifying the domain knowledge needed to understand protein sequences. Code is available on https://github.com/HKUNLP/RSA.

Chang Ma
Haiteng Zhao
Lin Zheng
Jiayi Xin
Qintong Li
Lijun Wu
Zhihong Deng
Yang Lu
Qi Liu
Lingpeng Kong


Semantic Importance-Aware Communications Using Pre-trained Language Models

Abstract: This letter proposes a semantic importance-aware communication (SIAC) scheme using pre-trained language models (e.g., ChatGPT, BERT, etc.). Specifically, we propose a cross-layer design with a pre-trained language model embedded in/connected by the cross-layer manager. The pre-trained language model is utilized to quantify the semantic importance of data frames. Based on the quantified semantic importance, we investigate semantic importance-aware power allocation. Unlike existing deep joint source-channel coding (Deep-JSCC)-based semantic communication schemes, SIAC can be directly embedded into current communication systems by only introducing a cross-layer manager. Our experimental results show that the proposed SIAC scheme can achieve lower semantic loss than existing equal-priority communications.

Shuaishuai Guo
Yanhu Wang
Shujing Li
Nasir Saeed


NodeCoder: a graph-based machine learning platform to predict active sites of modeled protein structures

Abstract: While accurate protein structure predictions are now available for nearly every observed protein sequence, predicted structures lack much of the functional context offered by experimental structure determination. We address this gap with NodeCoder, a task-independent platform that maps residue-based datasets onto 3D protein structures, embeds the resulting structural feature into a contact network, and models residue classification tasks with a Graph Convolutional Network (GCN). We demonstrate the versatility of this strategy by modeling six separate tasks, with some labels derived from other experimental structure studies (ligand, peptide, ion, and nucleic acid binding sites) and other labels derived from annotation databases (post-translational modification and transmembrane regions). Moreover, A NodeCoder model trained to identify ligand binding site residues was able to outperform P2Rank, a widely-used software developed specifically for ligand binding site detection. NodeCoder is available as an open-source python package at https://pypi.org/project/NodeCoder/.

Nasim Abdollahi
Seyed Ali Madani Tonekaboni
Jay Huang
Bo Wang
Stephen MacKinnon


Structure-informed Language Models Are Protein Designers

Abstract: 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)

Zaixiang Zheng
Yifan Deng
Dongyu Xue
Yi Zhou
Fei YE
Quanquan Gu


ExplainableFold: Understanding AlphaFold Prediction with Explainable AI

Abstract: This paper presents ExplainableFold, an explainable AI framework for protein structure prediction. Despite the success of AI-based methods such as AlphaFold in this field, the underlying reasons for their predictions remain unclear due to the black-box nature of deep learning models. To address this, we propose a counterfactual learning framework inspired by biological principles to generate counterfactual explanations for protein structure prediction, enabling a dry-lab experimentation approach. Our experimental results demonstrate the ability of ExplainableFold to generate high-quality explanations for AlphaFold's predictions, providing near-experimental understanding of the effects of amino acids on 3D protein structure. This framework has the potential to facilitate a deeper understanding of protein structures.


DiffSDS: A language diffusion model for protein backbone inpainting under geometric conditions and constraints

Abstract: Have you ever been troubled by the complexity and computational cost of SE(3) protein structure modeling and been amazed by the simplicity and power of language modeling? Recent work has shown promise in simplifying protein structures as sequences of protein angles; therefore, language models could be used for unconstrained protein backbone generation. Unfortunately, such simplification is unsuitable for the constrained protein inpainting problem, where the model needs to recover masked structures conditioned on unmasked ones, as it dramatically increases the computing cost of geometric constraints. To overcome this dilemma, we suggest inserting a hidden \textbf{a}tomic \textbf{d}irection \textbf{s}pace (\textbf{ADS}) upon the language model, converting invariant backbone angles into equivalent direction vectors and preserving the simplicity, called Seq2Direct encoder ($\text{Enc}_{s2d}$). Geometric constraints could be efficiently imposed on the newly introduced direction space. A Direct2Seq decoder ($\text{Dec}_{d2s}$) with mathematical guarantees is also introduced to develop a \textbf{SDS} ($\text{Enc}_{s2d}$+$\text{Dec}_{d2s}$) model. We apply the SDS model as the denoising neural network during the conditional diffusion process, resulting in a constrained generative model--\textbf{DiffSDS}. Extensive experiments show that the plug-and-play ADS could transform the language model into a strong structural model without loss of simplicity. More importantly, the proposed DiffSDS outperforms previous strong baselines by a large margin on the task of protein inpainting.


Beating the Best: Improving on AlphaFold2 at Protein Structure Prediction

Abstract: The goal of Protein Structure Prediction (PSP) problem is to predict a protein's 3D structure (confirmation) from its amino acid sequence. The problem has been a 'holy grail' of science since the Noble prize-winning work of Anfinsen demonstrated that protein conformation was determined by sequence. A recent and important step towards this goal was the development of AlphaFold2, currently the best PSP method. AlphaFold2 is probably the highest profile application of AI to science. Both AlphaFold2 and RoseTTAFold (another impressive PSP method) have been published and placed in the public domain (code & models). Stacking is a form of ensemble machine learning ML in which multiple baseline models are first learnt, then a meta-model is learnt using the outputs of the baseline level model to form a model that outperforms the base models. Stacking has been successful in many applications. We developed the ARStack PSP method by stacking AlphaFold2 and RoseTTAFold. ARStack significantly outperforms AlphaFold2. We rigorously demonstrate this using two sets of non-homologous proteins, and a test set of protein structures published after that of AlphaFold2 and RoseTTAFold. As more high quality prediction methods are published it is likely that ensemble methods will increasingly outperform any single method.

Abbi Abdel-Rehim
Oghenejokpeme Orhobor
Hang Lou
Hao Ni
Ross D. King


Ankh: Optimized Protein Language Model Unlocks General-Purpose Modelling

Abstract: 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.

Ahmed Elnaggar
Hazem Essam
Wafaa Salah-Eldin
Walid Moustafa
Mohamed Elkerdawy
Charlotte Rochereau
Burkhard Rost


Language Cognition and Language Computation -- Human and Machine Language Understanding

Abstract: Language understanding is a key scientific issue in the fields of cognitive and computer science. However, the two disciplines differ substantially in the specific research questions. Cognitive science focuses on analyzing the specific mechanism of the brain and investigating the brain's response to language; few studies have examined the brain's language system as a whole. By contrast, computer scientists focus on the efficiency of practical applications when choosing research questions but may ignore the most essential laws of language. Given these differences, can a combination of the disciplines offer new insights for building intelligent language models and studying language cognitive mechanisms? In the following text, we first review the research questions, history, and methods of language understanding in cognitive and computer science, focusing on the current progress and challenges. We then compare and contrast the research of language understanding in cognitive and computer sciences. Finally, we review existing work that combines insights from language cognition and language computation and offer prospects for future development trends.

Shaonan Wang
Nai Ding
Nan Lin
Jiajun Zhang
Chengqing Zong


On the Robustness of AlphaFold: A COVID-19 Case Study

Abstract: Protein folding neural networks (PFNNs) such as AlphaFold predict remarkably accurate structures of proteins compared to other approaches. However, the robustness of such networks has heretofore not been explored. This is particularly relevant given the broad social implications of such technologies and the fact that biologically small perturbations in the protein sequence do not generally lead to drastic changes in the protein structure. In this paper, we demonstrate that AlphaFold does not exhibit such robustness despite its high accuracy. This raises the challenge of detecting and quantifying the extent to which these predicted protein structures can be trusted. To measure the robustness of the predicted structures, we utilize (i) the root-mean-square deviation (RMSD) and (ii) the Global Distance Test (GDT) similarity measure between the predicted structure of the original sequence and the structure of its adversarially perturbed version. We prove that the problem of minimally perturbing protein sequences to fool protein folding neural networks is NP-complete. Based on the well-established BLOSUM62 sequence alignment scoring matrix, we generate adversarial protein sequences and show that the RMSD between the predicted protein structure and the structure of the original sequence are very large when the adversarial changes are bounded by (i) 20 units in the BLOSUM62 distance, and (ii) five residues (out of hundreds or thousands of residues) in the given protein sequence. In our experimental evaluation, we consider 111 COVID-19 proteins in the Universal Protein resource (UniProt), a central resource for protein data managed by the European Bioinformatics Institute, Swiss Institute of Bioinformatics, and the US Protein Information Resource. These result in an overall GDT similarity test score average of around 34%, demonstrating a substantial drop in the performance of AlphaFold.

Ismail Alkhouri
Sumit Jha
Andre Beckus
George Atia
Alvaro Velasquez
Rickard Ewetz
Arvind Ramanathan
Susmit Jha


Reprogramming Pretrained Language Models for Protein Sequence Representation Learning

Abstract: Machine Learning-guided solutions for protein learning tasks have made significant headway in recent years. However, success in scientific discovery tasks is limited by the accessibility of well-defined and labeled in-domain data. To tackle the low-data constraint, recent adaptions of deep learning models pretrained on millions of protein sequences have shown promise; however, the construction of such domain-specific large-scale model is computationally expensive. Here, we propose Representation Learning via Dictionary Learning (R2DL), an end-to-end representation learning framework in which we reprogram deep models for alternate-domain tasks that can perform well on protein property prediction with significantly fewer training samples. R2DL reprograms a pretrained English language model to learn the embeddings of protein sequences, by learning a sparse linear mapping between English and protein sequence vocabulary embeddings. Our model can attain better accuracy and significantly improve the data efficiency by up to $10^5$ times over the baselines set by pretrained and standard supervised methods. To this end, we reprogram an off-the-shelf pre-trained English language transformer and benchmark it on a set of protein physicochemical prediction tasks (secondary structure, stability, homology, stability) as well as on a biomedically relevant set of protein function prediction tasks (antimicrobial, toxicity, antibody affinity).


Protein Structure Prediction until CASP15

Abstract: In Dec 2020, the results of AlphaFold2 were presented at CASP14, sparking a revolution in the field of protein structure predictions. For the first time, a purely computational method could challenge experimental accuracy for structure prediction of single protein domains. The code of AlphaFold2 was released in the summer of 2021, and since then, it has been shown that it can be used to accurately predict the structure of most (ordered) proteins and many protein-protein interactions. It has also sparked an explosion of development in the field, improving AI-based methods to predict protein complexes, disordered regions, and protein design. Here I will review some of the inventions sparked by the release of AlphaFold.


Prompting Is Programming: A Query Language for Large Language Models

Abstract: Large language models have demonstrated outstanding performance on a wide range of tasks such as question answering and code generation. On a high level, given an input, a language model can be used to automatically complete the sequence in a statistically-likely way. Based on this, users prompt these models with language instructions or examples, to implement a variety of downstream tasks. Advanced prompting methods can even imply interaction between the language model, a user, and external tools such as calculators. However, to obtain state-of-the-art performance or adapt language models for specific tasks, complex task- and model-specific programs have to be implemented, which may still require ad-hoc interaction. Based on this, we present the novel idea of Language Model Programming (LMP). LMP generalizes language model prompting from pure text prompts to an intuitive combination of text prompting and scripting. Additionally, LMP allows constraints to be specified over the language model output. This enables easy adaption to many tasks while abstracting language model internals and providing high-level semantics. To enable LMP, we implement LMQL(short for Language Model Query Language), which leverages the constraints and control flow from an LMP prompt to generate an efficient inference procedure that minimizes the number of expensive calls to the underlying language model. We show that LMQL can capture a wide range of state-of-the-art prompting methods in an intuitive way, especially facilitating interactive flows that are challenging to implement with existing high-level APIs. Our evaluation shows that we retain or increase the accuracy on several downstream tasks, while also significantly reducing the required amount of computation or cost in the case of pay-to-use APIs (26-85% cost savings).

Luca Beurer-Kellner
Marc Fischer
Martin Vechev


Integration of Pre-trained Protein Language Models into Geometric Deep Learning Networks

Abstract: Geometric deep learning has recently achieved great success in non-Euclidean domains, and learning on 3D structures of large biomolecules is emerging as a distinct research area. However, its efficacy is largely constrained due to the limited quantity of structural data. Meanwhile, protein language models trained on substantial 1D sequences have shown burgeoning capabilities with scale in a broad range of applications. Several previous studies consider combining these different protein modalities to promote the representation power of geometric neural networks, but fail to present a comprehensive understanding of their benefits. In this work, we integrate the knowledge learned by well-trained protein language models into several state-of-the-art geometric networks and evaluate a variety of protein representation learning benchmarks, including protein-protein interface prediction, model quality assessment, protein-protein rigid-body docking, and binding affinity prediction. Our findings show an overall improvement of 20% over baselines. Strong evidence indicates that the incorporation of protein language models' knowledge enhances geometric networks' capacity by a significant margin and can be generalized to complex tasks.

Fang Wu
Lirong Wu
Dragomir Radev
Jinbo Xu
Stan Z. Li


SOLD: Sinhala Offensive Language Dataset

Abstract: The widespread of offensive content online, such as hate speech and cyber-bullying, is a global phenomenon. This has sparked interest in the artificial intelligence (AI) and natural language processing (NLP) communities, motivating the development of various systems trained to detect potentially harmful content automatically. These systems require annotated datasets to train the machine learning (ML) models. However, with a few notable exceptions, most datasets on this topic have dealt with English and a few other high-resource languages. As a result, the research in offensive language identification has been limited to these languages. This paper addresses this gap by tackling offensive language identification in Sinhala, a low-resource Indo-Aryan language spoken by over 17 million people in Sri Lanka. We introduce the Sinhala Offensive Language Dataset (SOLD) and present multiple experiments on this dataset. SOLD is a manually annotated dataset containing 10,000 posts from Twitter annotated as offensive and not offensive at both sentence-level and token-level, improving the explainability of the ML models. SOLD is the first large publicly available offensive language dataset compiled for Sinhala. We also introduce SemiSOLD, a larger dataset containing more than 145,000 Sinhala tweets, annotated following a semi-supervised approach.

Tharindu Ranasinghe
Isuri Anuradha
Damith Premasiri
Kanishka Silva
Hansi Hettiarachchi
Lasitha Uyangodage
Marcos Zampieri


Protein Language Models and Structure Prediction: Connection and Progression

Abstract: The prediction of protein structures from sequences is an important task for function prediction, drug design, and related biological processes understanding. Recent advances have proved the power of language models (LMs) in processing the protein sequence databases, which inherit the advantages of attention networks and capture useful information in learning representations for proteins. The past two years have witnessed remarkable success in tertiary protein structure prediction (PSP), including evolution-based and single-sequence-based PSP. It seems that instead of using energy-based models and sampling procedures, protein language model (pLM)-based pipelines have emerged as mainstream paradigms in PSP. Despite the fruitful progress, the PSP community needs a systematic and up-to-date survey to help bridge the gap between LMs in the natural language processing (NLP) and PSP domains and introduce their methodologies, advancements and practical applications. To this end, in this paper, we first introduce the similarities between protein and human languages that allow LMs extended to pLMs, and applied to protein databases. Then, we systematically review recent advances in LMs and pLMs from the perspectives of network architectures, pre-training strategies, applications, and commonly-used protein databases. Next, different types of methods for PSP are discussed, particularly how the pLM-based architectures function in the process of protein folding. Finally, we identify challenges faced by the PSP community and foresee promising research directions along with the advances of pLMs. This survey aims to be a hands-on guide for researchers to understand PSP methods, develop pLMs and tackle challenging problems in this field for practical purposes.

Bozhen Hu
Jun Xia
Jiangbin Zheng
Cheng Tan
Yufei Huang
Yongjie Xu
Stan Z. Li


An Overview of Indian Spoken Language Recognition from Machine Learning Perspective

Abstract: Automatic spoken language identification (LID) is a very important research field in the era of multilingual voice-command-based human-computer interaction (HCI). A front-end LID module helps to improve the performance of many speech-based applications in the multilingual scenario. India is a populous country with diverse cultures and languages. The majority of the Indian population needs to use their respective native languages for verbal interaction with machines. Therefore, the development of efficient Indian spoken language recognition systems is useful for adapting smart technologies in every section of Indian society. The field of Indian LID has started gaining momentum in the last two decades, mainly due to the development of several standard multilingual speech corpora for the Indian languages. Even though significant research progress has already been made in this field, to the best of our knowledge, there are not many attempts to analytically review them collectively. In this work, we have conducted one of the very first attempts to present a comprehensive review of the Indian spoken language recognition research field. In-depth analysis has been presented to emphasize the unique challenges of low-resource and mutual influences for developing LID systems in the Indian contexts. Several essential aspects of the Indian LID research, such as the detailed description of the available speech corpora, the major research contributions, including the earlier attempts based on statistical modeling to the recent approaches based on different neural network architectures, and the future research trends are discussed. This review work will help assess the state of the present Indian LID research by any active researcher or any research enthusiasts from related fields.

ACM Transactions on Asian and Low-Resource Language Information Processing, Volume 21, Issue 6 November 2022, Article No 128


Applying Deep Reinforcement Learning to the HP Model for Protein Structure Prediction

Abstract: A central problem in computational biophysics is protein structure prediction, i.e., finding the optimal folding of a given amino acid sequence. This problem has been studied in a classical abstract model, the HP model, where the protein is modeled as a sequence of H (hydrophobic) and P (polar) amino acids on a lattice. The objective is to find conformations maximizing H-H contacts. It is known that even in this reduced setting, the problem is intractable (NP-hard). In this work, we apply deep reinforcement learning (DRL) to the two-dimensional HP model. We can obtain the conformations of best known energies for benchmark HP sequences with lengths from 20 to 50. Our DRL is based on a deep Q-network (DQN). We find that a DQN based on long short-term memory (LSTM) architecture greatly enhances the RL learning ability and significantly improves the search process. DRL can sample the state space efficiently, without the need of manual heuristics. Experimentally we show that it can find multiple distinct best-known solutions per trial. This study demonstrates the effectiveness of deep reinforcement learning in the HP model for protein folding.

Kaiyuan Yang
Houjing Huang
Olafs Vandans
Adithya Murali
Fujia Tian
Roland H. C. Yap
Liang Dai


Protein language model rescue mutations highlight variant effects and structure in clinically relevant genes

Abstract: 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.


Radiomics-enhanced Deep Multi-task Learning for Outcome Prediction in Head and Neck Cancer

Abstract: Outcome prediction is crucial for head and neck cancer patients as it can provide prognostic information for early treatment planning. Radiomics methods have been widely used for outcome prediction from medical images. However, these methods are limited by their reliance on intractable manual segmentation of tumor regions. Recently, deep learning methods have been proposed to perform end-to-end outcome prediction so as to remove the reliance on manual segmentation. Unfortunately, without segmentation masks, these methods will take the whole image as input, such that makes them difficult to focus on tumor regions and potentially unable to fully leverage the prognostic information within the tumor regions. In this study, we propose a radiomics-enhanced deep multi-task framework for outcome prediction from PET/CT images, in the context of HEad and neCK TumOR segmentation and outcome prediction challenge (HECKTOR 2022). In our framework, our novelty is to incorporate radiomics as an enhancement to our recently proposed Deep Multi-task Survival model (DeepMTS). The DeepMTS jointly learns to predict the survival risk scores of patients and the segmentation masks of tumor regions. Radiomics features are extracted from the predicted tumor regions and combined with the predicted survival risk scores for final outcome prediction, through which the prognostic information in tumor regions can be further leveraged. Our method achieved a C-index of 0.681 on the testing set, placing the 2nd on the leaderboard with only 0.00068 lower in C-index than the 1st place.

Mingyuan Meng
Lei Bi
Dagan Feng
Jinman Kim

Head and Neck Tumor Segmentation and Outcome Prediction (HECKTOR 2022), pp.135-143


AfroLM: A Self-Active Learning-based Multilingual Pretrained Language Model for 23 African Languages

Abstract: In recent years, multilingual pre-trained language models have gained prominence due to their remarkable performance on numerous downstream Natural Language Processing tasks (NLP). However, pre-training these large multilingual language models requires a lot of training data, which is not available for African Languages. Active learning is a semi-supervised learning algorithm, in which a model consistently and dynamically learns to identify the most beneficial samples to train itself on, in order to achieve better optimization and performance on downstream tasks. Furthermore, active learning effectively and practically addresses real-world data scarcity. Despite all its benefits, active learning, in the context of NLP and especially multilingual language models pretraining, has received little consideration. In this paper, we present AfroLM, a multilingual language model pretrained from scratch on 23 African languages (the largest effort to date) using our novel self-active learning framework. Pretrained on a dataset significantly (14x) smaller than existing baselines, AfroLM outperforms many multilingual pretrained language models (AfriBERTa, XLMR-base, mBERT) on various NLP downstream tasks (NER, text classification, and sentiment analysis). Additional out-of-domain sentiment analysis experiments show that \textbf{AfroLM} is able to generalize well across various domains. We release the code source, and our datasets used in our framework at https://github.com/bonaventuredossou/MLM_AL.

Bonaventure F. P. Dossou
Atnafu Lambebo Tonja
Oreen Yousuf
Salomey Osei
Abigail Oppong
Iyanuoluwa Shode
Oluwabusayo Olufunke Awoyomi
Chris Chinenye Emezue


An Efficient MCMC Approach to Energy Function Optimization in Protein Structure Prediction

Abstract: Protein structure prediction is a critical problem linked to drug design, mutation detection, and protein synthesis, among other applications. To this end, evolutionary data has been used to build contact maps which are traditionally minimized as energy functions via gradient descent based schemes like the L-BFGS algorithm. In this paper we present what we call the Alternating Metropolis-Hastings (AMH) algorithm, which (a) significantly improves the performance of traditional MCMC methods, (b) is inherently parallelizable allowing significant hardware acceleration using GPU, and (c) can be integrated with the L-BFGS algorithm to improve its performance. The algorithm shows an improvement in energy of found structures of 8.17% to 61.04% (average 38.9%) over traditional MH and 0.53% to 17.75% (average 8.9%) over traditional MH with intermittent noisy restarts, tested across 9 proteins from recent CASP competitions. We go on to map the Alternating MH algorithm to a GPGPU which improves sampling rate by 277x and improves simulation time to a low energy protein prediction by 7.5x to 26.5x over CPU. We show that our approach can be incorporated into state-of-the-art protein prediction pipelines by applying it to both trRosetta2's energy function and the distogram component of Alphafold1's energy function. Finally, we note that specially designed probabilistic computers (or p-computers) can provide even better performance than GPUs for MCMC algorithms like the one discussed here.

Lakshmi A. Ghantasala
Risi Jaiswal
Supriyo Datta


Autoregressive Structured Prediction with Language Models

Abstract: Recent years have seen a paradigm shift in NLP towards using pretrained language models ({PLM}) for a wide range of tasks. However, there are many difficult design decisions to represent structures (e.g. tagged text, coreference chains) in a way such that they can be captured by PLMs. Prior work on structured prediction with PLMs typically flattens the structured output into a sequence, which limits the quality of structural information being learned and leads to inferior performance compared to classic discriminative models. In this work, we describe an approach to model structures as sequences of actions in an autoregressive manner with PLMs, allowing in-structure dependencies to be learned without any loss. Our approach achieves the new state-of-the-art on all the structured prediction tasks we looked at, namely, named entity recognition, end-to-end relation extraction, and coreference resolution.

Tianyu Liu
Yuchen Jiang
Nicholas Monath
Ryan Cotterell
Mrinmaya Sachan


AlphaFold Distillation for Protein Design

Abstract: Inverse protein folding, the process of designing sequences that fold into a specific 3D structure, is crucial in bio-engineering and drug discovery. Traditional methods rely on experimentally resolved structures, but these cover only a small fraction of protein sequences. Forward folding models like AlphaFold offer a potential solution by accurately predicting structures from sequences. However, these models are too slow for integration into the optimization loop of inverse folding models during training. To address this, we propose using knowledge distillation on folding model confidence metrics, such as pTM or pLDDT scores, to create a faster and end-to-end differentiable distilled model. This model can then be used as a structure consistency regularizer in training the inverse folding model. Our technique is versatile and can be applied to other design tasks, such as sequence-based protein infilling. Experimental results show that our method outperforms non-regularized baselines, yielding up to 3% improvement in sequence recovery and up to 45% improvement in protein diversity while maintaining structural consistency in generated sequences. Code is available at https://github.com/IBM/AFDistill

Igor Melnyk
Aurelie Lozano
Payel Das
Vijil Chenthamarakshan


State-specific protein-ligand complex structure prediction with a multi-scale deep generative model

Abstract: The binding complexes formed by proteins and small molecule ligands are ubiquitous and critical to life. Despite recent advancements in protein structure prediction, existing algorithms are so far unable to systematically predict the binding ligand structures along with their regulatory effects on protein folding. To address this discrepancy, we present NeuralPLexer, a computational approach that can directly predict protein-ligand complex structures solely using protein sequence and ligand molecular graph inputs. NeuralPLexer adopts a deep generative model to sample the 3D structures of the binding complex and their conformational changes at an atomistic resolution. The model is based on a diffusion process that incorporates essential biophysical constraints and a multi-scale geometric deep learning system to iteratively sample residue-level contact maps and all heavy-atom coordinates in a hierarchical manner. NeuralPLexer achieves state-of-the-art performance compared to all existing methods on benchmarks for both protein-ligand blind docking and flexible binding site structure recovery. Moreover, owing to its specificity in sampling both ligand-free-state and ligand-bound-state ensembles, NeuralPLexer consistently outperforms AlphaFold2 in terms of global protein structure accuracy on both representative structure pairs with large conformational changes (average TM-score=0.93) and recently determined ligand-binding proteins (average TM-score=0.89). Case studies reveal that the predicted conformational variations are consistent with structure determination experiments for important targets, including human KRAS$^\textrm{G12C}$, ketol-acid reductoisomerase, and purine GPCRs. Our study suggests that a data-driven approach can capture the structural cooperativity between proteins and small molecules, showing promise in accelerating the design of enzymes, drug molecules, and beyond.

Zhuoran Qiao
Weili Nie
Arash Vahdat
Thomas F. Miller
Anima Anandkumar


Secondary Protein Structure Prediction Using Neural Networks

Abstract: In this paper we experiment with using neural network structures to predict a protein's secondary structure (α helix positions) from only its primary structure (amino acid sequence). We implement a fully connected neural network (FCNN) and preform three experiments using that FCNN. Firstly, we do a cross-species comparison of models trained and tested on mouse and human datasets. Secondly, we test the impact of varying the length of protein sequence we input into the model. Thirdly, we compare custom error functions designed to focus on the center of the input window. At the end of paper we propose a alternative, recurrent neural network model which can be applied to the problem.


HelixFold-Single: MSA-free Protein Structure Prediction by Using Protein Language Model as an Alternative

Abstract: AI-based protein structure prediction pipelines, such as AlphaFold2, have achieved near-experimental accuracy. These advanced pipelines mainly rely on Multiple Sequence Alignments (MSAs) as inputs to learn the co-evolution information from the homologous sequences. Nonetheless, searching MSAs from protein databases is time-consuming, usually taking dozens of minutes. Consequently, we attempt to explore the limits of fast protein structure prediction by using only primary sequences of proteins. HelixFold-Single is proposed to combine a large-scale protein language model with the superior geometric learning capability of AlphaFold2. Our proposed method, HelixFold-Single, first pre-trains a large-scale protein language model (PLM) with thousands of millions of primary sequences utilizing the self-supervised learning paradigm, which will be used as an alternative to MSAs for learning the co-evolution information. Then, by combining the pre-trained PLM and the essential components of AlphaFold2, we obtain an end-to-end differentiable model to predict the 3D coordinates of atoms from only the primary sequence. HelixFold-Single is validated in datasets CASP14 and CAMEO, achieving competitive accuracy with the MSA-based methods on the targets with large homologous families. Furthermore, HelixFold-Single consumes much less time than the mainstream pipelines for protein structure prediction, demonstrating its potential in tasks requiring many predictions. The code of HelixFold-Single is available at https://github.com/PaddlePaddle/PaddleHelix/tree/dev/apps/protein_folding/helixfold-single, and we also provide stable web services on https://paddlehelix.baidu.com/app/drug/protein-single/forecast.

Xiaomin Fang
Fan Wang
Lihang Liu
Jingzhou He
Dayong Lin
Yingfei Xiang
Xiaonan Zhang
Hua Wu
Hui Li
Le Song