Protein interactions are important in a broad range of biological processes. Traditionally, computational methods have been developed to automatically predict protein interface from hand-crafted features. Recent approaches employ deep neural networks and predict the interaction of each amino acid pair independently. However, these methods do not incorporate the important sequential information from amino acid chains and the high-order pairwise interactions. Intuitively, the prediction of an amino acid pair should depend on both their features and the information of other amino acid pairs. In this work, we propose to formulate the protein interface prediction as a 2D dense prediction problem. In addition, we propose a novel deep model to incorporate the sequential information and high-order pairwise interactions to perform interface predictions. We represent proteins as graphs and employ graph neural networks to learn node features. Then we propose the sequential modeling method to incorporate the sequential information and reorder the feature matrix. Next, we incorporate high-order pairwise interactions to generate a 3D tensor containing different pairwise interactions. Finally, we employ convolutional neural networks to perform 2D dense predictions. Experimental results on multiple benchmarks demonstrate that our proposed method can consistently improve the protein interface prediction performance.
Computational methods for predicting the interface contacts between proteins come highly sought after for drug discovery as they can significantly advance the accuracy of alternative approaches, such as protein-protein docking, protein function analysis tools, and other computational methods for protein bioinformatics. In this work, we present the Geometric Transformer, a novel geometry-evolving graph transformer for rotation and translation-invariant protein interface contact prediction, packaged within DeepInteract, an end-to-end prediction pipeline. DeepInteract predicts partner-specific pr…
Despite an explosion in the number of experimentally determined, atomically detailed structures of biomolecules, many critical tasks in structural biology remain data-limited. Whether performance in such tasks can be improved by using large repositories of tangentially related structural data remains an open question. To address this question, we focused on a central problem in biology: predicting how proteins interact with one another---that is, which surfaces of one protein bind to those of another protein. We built a training dataset, the Database of Interacting Protein Structures (DIPS), t…
A Multimodal Human Protein Embeddings Database: DeepDrug Protein Embeddings Bank (DPEB)
Computer Science, Louisiana State University（计算机科学，路易斯安那州立大学）；Computer Science, Furman University（计算机科学，福兰明大学）；Environmental Sciences and Center for Computation and Technology, Louisiana State University（环境科学与计算技术中心，路易斯安那州立大学）
Columbia University（哥伦比亚大学）；Cornell University（康奈尔大学）
Proteins are the major building blocks of life, and actuators of almost all chemical and biophysical events in living organisms. Their native structures in turn enable their biological functions which have a fundamental role in drug design. This motivates predicting the structure of a protein from its sequence of amino acids, a fundamental problem in computational biology. In this work, we demonstrate state-of-the-art protein structure prediction (PSP) results using embeddings and deep learning models for prediction of backbone atom distance matrices and torsion angles. We recover 3D coordinat…
Lawrence Berkeley National Laboratory（劳伦斯伯克利国家实验室）；University of California, Berkeley（加州大学伯克利分校）
Understanding protein structure-function relationships is a key challenge in computational biology, with applications across the biotechnology and pharmaceutical industries. While it is known that protein structure directly impacts protein function, many functional prediction tasks use only protein sequence. In this work, we isolate protein structure to make functional annotations for proteins in the Protein Data Bank in order to study the expressiveness of different structure-based prediction schemes. We present PersGNN - an end-to-end trainable deep learning model that combines graph represe…
Graphs as a type of data structure have recently attracted significant attention. Representation learning of geometric graphs has achieved great success in many fields including molecular, social, and financial networks. It is natural to present proteins as graphs in which nodes represent the residues and edges represent the pairwise interactions between residues. However, 3D protein structures have rarely been studied as graphs directly. The challenges include: 1) Proteins are complex macromolecules composed of thousands of atoms making them much harder to model than micro-molecules. 2) Captu…
Rigid Protein-Protein Docking via Equivariant Elliptic-Paraboloid Interface Prediction
Tsinghua University（清华大学）；Institute for AI Industry Research (AIR), Tsinghua University（清华大学人工智能产业研究院）；Gaoling School of Artificial Intelligence, Renmin University of China（中国人民大学高瓴人工智能学院）；Beijing Key Laboratory of Big Data Management and Analysis Methods（北京大数据管理与分析方法重点实验室）
University of Missouri（密苏里大学）；Oak Ridge National Laboratory（橡树岭国家实验室）
How and where proteins interface with one another can ultimately impact the proteins' functions along with a range of other biological processes. As such, precise computational methods for protein interface prediction (PIP) come highly sought after as they could yield significant advances in drug discovery and design as well as protein function analysis. However, the traditional benchmark dataset for this task, Docking Benchmark 5 (DB5), contains only a modest 230 complexes for training, validating, and testing different machine learning algorithms. In this work, we expand on a dataset recentl…
Bioinformatics Research Group (BioRG)（生物信息学研究组）；Knight Foundation School of Computing and Information Sciences（骑士基金会计算与信息科学学院）；Florida International University（佛罗里达国际大学）；Biomolecular Sciences Institute（生物分子科学研究所）
Latent Retrieval Augmented Generation of Cross-Domain Protein Binders
Dept. of Comp. Sci. & Tech., Tsinghua University（计算机科学与技术系，清华大学）；Institute for AIR, Tsinghua University（空气智能研究所，清华大学）；Gaoling School of Artificial Intelligence, Renmin University of China（北京理工大学人工智能学院）
California Institute of Technology（加州理工学院）；Google Deepmind（谷歌DeepMind）；Microsoft Research New England（微软新英格兰研究院）
Protein engineering seeks to identify protein sequences with optimized properties. When guided by machine learning, protein sequence generation methods can draw on prior knowledge and experimental efforts to improve this process. In this review, we highlight recent applications of machine learning to generate protein sequences, focusing on the emerging field of deep generative methods.
Center for Computational Engineering and Networking (CEN)（计算工程与网络中心（CEN））；Amrita School of Engineering（阿姆里塔工程学院）；Amrita Vishwa Vidyapeetham（阿姆里塔维什瓦维迪亚佩瑟姆大学）
The knowledge regarding the function of proteins is necessary as it gives a clear picture of biological processes. Nevertheless, there are many protein sequences found and added to the databases but lacks functional annotation. The laboratory experiments take a considerable amount of time for annotation of the sequences. This arises the need to use computational techniques to classify proteins based on their functions. In our work, we have collected the data from Swiss-Prot containing 40433 proteins which is grouped into 30 families. We pass it to recurrent neural network(RNN), long short term…
LS2N, Université de Nantes（南特大学LS2N实验室）；JFLI, CNRS, National Institute of Informatics（法国国家科学研究中心、国立情报学研究所JFLI联合实验室）；UFIP, Université de Nantes（南特大学UFIP实验室）
Biological data are extremely diverse, complex but also quite sparse. The recent developments in deep learning methods are offering new possibilities for the analysis of complex data. However, it is easy to be get a deep learning model that seems to have good results but is in fact either overfitting the training data or the validation data. In particular, the fact to overfit the validation data, called "information leak", is almost never treated in papers proposing deep learning models to predict protein-protein interactions (PPI). In this work, we compare two carefully designed deep learning…
Motivation: Drug discovery demands rapid quantification of compound-protein interaction (CPI). However, there is a lack of methods that can predict compound-protein affinity from sequences alone with high applicability, accuracy, and interpretability. Results: We present a seamless integration of domain knowledges and learning-based approaches. Under novel representations of structurally-annotated protein sequences, a semi-supervised deep learning model that unifies recurrent and convolutional neural networks has been proposed to exploit both unlabeled and labeled data, for jointly encoding mo…
Artificial neural networks (ANNs) have gained a well-deserved popularity among machine learning tools upon their recent successful applications in image- and sound processing and classification problems. ANNs have also been applied for predicting the family or function of a protein, knowing its residue sequence. Here we present two new ANNs with multi-label classification ability, showing impressive accuracy when classifying protein sequences into 698 UniProt families (AUC=99.99%) and 983 Gene Ontology classes (AUC=99.45%).
DeepProtein: Deep Learning Library and Benchmark for Protein Sequence Learning
Department of Computer Science ETH Zurich（计算机科学系 雪绒花大学）；National Key Laboratory for Novel Software Technology, School of Computer Science Nanjing University（新型软件技术国家重点实验室 计算机科学学院 南京大学）
Traditional machine learning vs. deep learning from dynamic graph representations of proteins' 3D folds in the task of protein structure classification
University of Notre Dame（圣母大学）；Eck Institute for Global Health, University of Notre Dame（圣母大学埃克全球健康研究所）；Interdisciplinary Center for Network Science & Applications, University of Notre Dame（圣母大学网络科学与应用跨学科中心）；University of Tennessee at Knoxville（田纳西大学诺克斯维尔分校）
As proteins with similar structures often have similar functions, analysis of protein structures can help predict protein functions and is thus important. We consider the problem of protein structure classification, which computationally classifies the structures of proteins into pre-defined groups. We develop a weighted network that depicts the protein structures, and more importantly, we propose the first graphlet-based measure that applies to weighted networks. Further, we develop a deep neural network (DNN) composed of both convolutional and recurrent layers to use this measure for classif…
Deep learning is catalyzing a scientific revolution fueled by big data, accessible toolkits, and powerful computational resources, impacting many fields including protein structural modeling. Protein structural modeling, such as predicting structure from amino acid sequence and evolutionary information, designing proteins toward desirable functionality, or predicting properties or behavior of a protein, is critical to understand and engineer biological systems at the molecular level. In this review, we summarize the recent advances in applying deep learning techniques to tackle problems in pro…
School of Electrical Engineering and Computer Science, Gwangju Institute of Science and Technology（光州科学技术院电气与计算机工程学院）
Identification of drug-target interactions (DTIs) plays a key role in drug discovery. The high cost and labor-intensive nature of in vitro and in vivo experiments have highlighted the importance of in silico-based DTI prediction approaches. In several computational models, conventional protein descriptors are shown to be not informative enough to predict accurate DTIs. Thus, in this study, we employ a convolutional neural network (CNN) on raw protein sequences to capture local residue patterns participating in DTIs. With CNN on protein sequences, our model performs better than previous protein…
Protein secondary structure is crucial to creating an information bridge between the primary and tertiary (3D) structures. Precise prediction of eight-state protein secondary structure (PSS) has significantly utilized in the structural and functional analysis of proteins in bioinformatics. Deep learning techniques have been recently applied in this research area and raised the eight-state (Q8) protein secondary structure prediction accuracy remarkably. Nevertheless, from a theoretical standpoint, there are still lots of rooms for improvement, specifically in the eight-state PSS prediction. In …
University of Toronto（多伦多大学）；Donnelly Centre for Cellular and Biomolecular Research（唐纳利细胞与生物分子研究中心）
Deep learning approaches have produced substantial breakthroughs in fields such as image classification and natural language processing and are making rapid inroads in the area of protein design. Many generative models of proteins have been developed that encompass all known protein sequences, model specific protein families, or extrapolate the dynamics of individual proteins. Those generative models can learn protein representations that are often more informative of protein structure and function than hand-engineered features. Furthermore, they can be used to quickly propose millions of nove…
King Abdullah University of Science and Technology（阿卜杜拉国王科技大学）
A large number of protein sequences are becoming available through the application of novel high-throughput sequencing technologies. Experimental functional characterization of these proteins is time-consuming and expensive, and is often only done rigorously for few selected model organisms. Computational function prediction approaches have been suggested to fill this gap. The functions of proteins are classified using the Gene Ontology (GO), which contains over 40,000 classes. Additionally, proteins have multiple functions, making function prediction a large-scale, multi-class, multi-label pr…
University of Athens（雅典大学）；Biomedical Sciences Research Center “Alexander Fleming”（亚历山大·弗莱明生物医学科学研究中心）
Despite considerable progress, ab initio protein structure prediction remains suboptimal. A crowdsourcing approach is the online puzzle video game Foldit, that provided several useful results that matched or even outperformed algorithmically computed solutions. Using Foldit, the WeFold crowd had several successful participations in the Critical Assessment of Techniques for Protein Structure Prediction. Based on the recent Foldit standalone version, we trained a deep reinforcement neural network called DeepFoldit to improve the score assigned to an unfolded protein, using the Q-learning method …
Toyota Technological Institute at Chicago（芝加哥丰田技术研究所）
Recently exciting progress has been made on protein contact prediction, but the predicted contacts for proteins without many sequence homologs is still of low quality and not very useful for de novo structure prediction. This paper presents a new deep learning method that predicts contacts by integrating both evolutionary coupling (EC) and sequence conservation information through an ultra-deep neural network formed by two deep residual networks. This deep neural network allows us to model very complex sequence-contact relationship as well as long-range inter-contact correlation. Our method gr…
Toyota Technological Institute at Chicago（芝加哥丰田工业大学）；University of Chicago（芝加哥大学）；University of Illinois at Urbana-Champaign（伊利诺伊大学厄巴纳-香槟分校）
Protein secondary structure (SS) prediction is important for studying protein structure and function. When only the sequence (profile) information is used as input feature, currently the best predictors can obtain ~80% Q3 accuracy, which has not been improved in the past decade. Here we present DeepCNF (Deep Convolutional Neural Fields) for protein SS prediction. DeepCNF is a Deep Learning extension of Conditional Neural Fields (CNF), which is an integration of Conditional Random Fields (CRF) and shallow neural networks. DeepCNF can model not only complex sequence-structure relationship by a d…
University of Missouri（密苏里大学）；Informatics Institute, University of Missouri（密苏里大学信息学研究所）
Protein quality assessment (QA) by ranking and selecting protein models has long been viewed as one of the major challenges for protein tertiary structure prediction. Especially, estimating the quality of a single protein model, which is important for selecting a few good models out of a large model pool consisting of mostly low-quality models, is still a largely unsolved problem. We introduce a novel single-model quality assessment method DeepQA based on deep belief network that utilizes a number of selected features describing the quality of a model from different perspectives, such as energ…
Motivation: Prediction of the interaction affinity between proteins and compounds is a major challenge in the drug discovery process. WideDTA is a deep-learning based prediction model that employs chemical and biological textual sequence information to predict binding affinity. Results: WideDTA uses four text-based information sources, namely the protein sequence, ligand SMILES, protein domains and motifs, and maximum common substructure words to predict binding affinity. WideDTA outperformed one of the state of the art deep learning methods for drug-target binding affinity prediction, DeepDTA…
Predicting protein properties such as solvent accessibility and secondary structure from its primary amino acid sequence is an important task in bioinformatics. Recently, a few deep learning models have surpassed the traditional window based multilayer perceptron. Taking inspiration from the image classification domain we propose a deep convolutional neural network architecture, MUST-CNN, to predict protein properties. This architecture uses a novel multilayer shift-and-stitch (MUST) technique to generate fully dense per-position predictions on protein sequences. Our model is significantly sim…
Introduction: The extracellular matrix (ECM) is a networkof proteins and carbohydrates that has a structural and bio-chemical function. The ECM plays an important role in dif-ferentiation, migration and signaling. Several studies havepredicted ECM proteins using machine learning algorithmssuch as Random Forests, K-nearest neighbours and supportvector machines but is yet to be explored using deep learn-ing. Method: DeepECMP was developed using several previ-ously used ECM datasets, asymmetric undersampling andan ensemble of 11 feed-forward neural networks. Results: The performance of DeepECMP w…
Lawrence Livermore National Laboratory（劳伦斯利弗莫尔国家实验室）
Improved understanding of the relation between the behavior of RAS and RAF proteins and the local lipid environment in the cell membrane is critical for getting insights into the mechanisms underlying cancer formation. In this work, we employ deep learning (DL) to learn this relationship by predicting protein orientational states of RAS and RAS-RAF protein complexes with respect to the lipid membrane based on the lipid densities around the protein domains from coarse-grained (CG) molecular dynamics (MD) simulations. Our DL model can predict six protein states with an overall accuracy of over 8…
Information Technologies Institute, Centre for Research and Technology Hellas（希腊研究与技术中心信息技术研究所）
The knowledge of potentially druggable binding sites on proteins is an important preliminary step towards the discovery of novel drugs. The computational prediction of such areas can be boosted by following the recent major advances in the deep learning field and by exploiting the increasing availability of proper data. In this paper, a novel computational method for the prediction of potential binding sites is proposed, called DeepSurf. DeepSurf combines a surface-based representation, where a number of 3D voxelized grids are placed on the protein's surface, with state-of-the-art deep learnin…
Identifying novel functional protein structures is at the heart of molecular engineering and molecular biology, requiring an often computationally exhaustive search. We introduce the use of a Deep Convolutional Generative Adversarial Network (DCGAN) to classify protein structures based on their functionality by encoding each sample in a grid object structure using three features in each object: the generic atom type, the position atom type, and its occupancy relative to a given atom. We train DCGAN on 3-dimensional (3D) decoy and native protein structures in order to generate and discriminate …
Deep Learning and big data have shown tremendous success in bioinformatics and computational biology in recent years; artificial intelligence methods have also significantly contributed in the task of protein function classification. This review paper analyzes the recent developments in approaches for the task of predicting protein function using deep learning. We explain the importance of determining the protein function and why automating the following task is crucial. Then, after reviewing the widely used deep learning techniques for this task, we continue our review and highlight the emerg…
Harvard University（哈佛大学）；Broad Institute of MIT and Harvard（麻省理工学院和哈佛大学博德研究所）；Harvard Data Science（哈佛数据科学研究院）
Spatial context is central to understanding health and disease. Yet reference protein interaction networks lack such contextualization, thereby limiting the study of where protein interactions likely occur in the human body and how they may be altered in disease. Contextualized protein interactions could better characterize genes with disease-specific interactions and elucidate diseases' manifestation in specific cell types. Here, we introduce AWARE, a graph neural message passing approach to inject cellular and tissue context into protein embeddings. AWARE optimizes for a multi-scale embeddin…
Motivation Protein fold recognition is an important problem in structural bioinformatics. Almost all traditional fold recognition methods use sequence (homology) comparison to indirectly predict the fold of a tar get protein based on the fold of a template protein with known structure, which cannot explain the relationship between sequence and fold. Only a few methods had been developed to classify protein sequences into a small number of folds due to methodological limitations, which are not generally useful in practice. Results We develop a deep 1D-convolution neural network (DeepSF) to dire…
David R. Cheriton School of Computer Science, University of Waterloo（滑铁卢大学 David R. Cheriton 计算机科学学院）；Bioinformatics Solutions Inc.（Bioinformatics Solutions 公司）
Proteins are the main workhorses of biological functions in a cell, a tissue, or an organism. Identification and quantification of proteins in a given sample, e.g. a cell type under normal/disease conditions, are fundamental tasks for the understanding of human health and disease. In this paper, we present DeepNovo, a deep learning-based tool to address the problem of protein identification from tandem mass spectrometry data. The idea was first proposed in the context of de novo peptide sequencing [1] in which convolutional neural networks and recurrent neural networks were applied to predict …
Saudi Electronic University（沙特电子大学）；The Commonwealth Scientific and Industrial Research Organisation（澳大利亚联邦科学与工业研究组织）；The Australian National University（澳大利亚国立大学）；University of Technology Sydney（悉尼科技大学）；the University of Western Australia（西澳大利亚大学）
Accurate localization of proteins from fluorescence microscopy images is challenging due to the inter-class similarities and intra-class disparities introducing grave concerns in addressing multi-class classification problems. Conventional machine learning-based image prediction pipelines rely heavily on pre-processing such as normalization and segmentation followed by hand-crafted feature extraction to identify useful, informative, and application-specific features. Here, we demonstrate that deep learning-based pipelines can effectively classify protein images from different datasets. We prop…
Composed of amino acid chains that influence how they fold and thus dictating their function and features, proteins are a class of macromolecules that play a central role in major biological processes and are required for the structure, function, and regulation of the body's tissues. Understanding protein functions is vital to the development of therapeutics and precision medicine, and hence the ability to classify proteins and their functions based on measurable features is crucial; indeed, the automatic inference of a protein's properties from its sequence of amino acids, known as its primar…
Oak Ridge National Laboratory（橡树岭国家实验室）；Rutgers University（罗格斯大学）；Argonne National Laboratory（阿贡国家实验室）；Brookhaven National Laboratory（布鲁克海文国家实验室）
Simulations of biological macromolecules play an important role in understanding the physical basis of a number of complex processes such as protein folding. Even with increasing computational power and evolution of specialized architectures, the ability to simulate protein folding at atomistic scales still remains challenging. This stems from the dual aspects of high dimensionality of protein conformational landscapes, and the inability of atomistic molecular dynamics (MD) simulations to sufficiently sample these landscapes to observe folding events. Machine learning/deep learning (ML/DL) tec…
Department of Electrical；Computer Engineering, Texas A\&M University, College Station, TX 77843, United States；Department of Computer Science；Engineering, Texas A\&M University, College Station, TX 77843, United States
Predicting compound-protein affinity is critical for accelerating drug discovery. Recent progress made by machine learning focuses on accuracy but leaves much to be desired for interpretability. Through molecular contacts underlying affinities, our large-scale interpretability assessment finds commonly-used attention mechanisms inadequate. We thus formulate a hierarchical multi-objective learning problem whose predicted contacts form the basis for predicted affinities. We further design a physics-inspired deep relational network, DeepRelations, with intrinsically explainable architecture. Spec…
National Center for Biotechnology Information（国家生物技术信息中心）；National Library of Medicine（国家医学图书馆）；National Institutes of Health（国立卫生研究院）
State-of-the-art methods for protein-protein interaction (PPI) extraction are primarily feature-based or kernel-based by leveraging lexical and syntactic information. But how to incorporate such knowledge in the recent deep learning methods remains an open question. In this paper, we propose a multichannel dependency-based convolutional neural network model (McDepCNN). It applies one channel to the embedding vector of each word in the sentence, and another channel to the embedding vector of the head of the corresponding word. Therefore, the model can use richer information obtained from differ…
ETH Zurich（苏黎世联邦理工学院）；Goethe University Frankfurt（法兰克福大学）；Tokyo Metropolitan University（东京都立大学）
Nuclear Magnetic Resonance (NMR) spectroscopy is one of the major techniques in structural biology with over 11,800 protein structures deposited in the Protein Data Bank. NMR can elucidate structures and dynamics of small and medium size proteins in solution, living cells, and solids, but has been limited by the tedious data analysis process. It typically requires weeks or months of manual work of a trained expert to turn NMR measurements into a protein structure. Automation of this process is an open problem, formulated in the field over 30 years ago. Here, we present a solution to this chall…
Toyota Technological Institute at Chicago（芝加哥丰田技术研究所）；University of Chicago（芝加哥大学）；University of Hong Kong（香港大学）
Computational prediction of membrane protein (MP) structures is very challenging partially due to lack of sufficient solved structures for homology modeling. Recently direct evolutionary coupling analysis (DCA) sheds some light on protein contact prediction and accordingly, contact-assisted folding, but DCA is effective only on some very large-sized families since it uses information only in a single protein family. This paper presents a deep transfer learning method that can significantly improve MP contact prediction by learning contact patterns and complex sequence-contact relationship from…
