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In the binding process between proteins and ligand molecules, water molecules play a pivotal role by forming hydrogen bonds that enable proteins and ligand molecules to bind more strongly. However, current methodologies for predicting binding affinity overlook the importance of water molecules. Therefore, we developed a model called GraphWater-Net, specifically designed for predicting protein-ligand binding affinity, by incorporating water molecules. GraphWater-Net employs topological structures to represent protein atoms, ligand atoms and water molecules, and their interactions. Leveraging the Graphormer network, the model extracts interaction features between nodes within the topology, alongside the interaction features of edges and nodes. Subsequently, it generates embeddings with attention weights, inputs them into a Softmax function for regression prediction, and ultimately outputs the predicted binding affinity value. Experimental results on the Comparative Assessment of Scoring Functions (CASF) 2016 test set show that the introduction of water molecules into the complex significantly improves the prediction performance of the proposed model for protein and ligand binding affinity. Specifically, the Pearson correlation coefficient ( R p ) exceeds that of current state-of-the-art methods by a margin of 0.022 to 0.129. By integrating water molecules, GraphWater-Net has the potential to facilitate the rational design of protein-ligand interactions and aid in drug discovery.

Proteins maintain the functional order of cell in life by interacting with other proteins. Determination of protein complex structural information gives biological insights for the research of diseases and drugs. Recently, a breakthrough has been made in protein monomer structure prediction. However, due to the limited number of the known protein structure and homologous sequences of complexes, the prediction of residue-residue contacts on hetero-dimer interfaces is still a challenge. In this study, we have developed a deep learning framework for inferring inter-protein residue contacts from sequential information, called HDIContact. We utilized transfer learning strategy to produce Multiple Sequence Alignment (MSA) two-dimensional (2D) embedding based on patterns of concatenated MSA, which could reduce the influence of noise on MSA caused by mismatched sequences or less homology. For MSA 2D embedding, HDIContact took advantage of Bi-directional Long Short-Term Memory (BiLSTM) with two-channel to capture 2D context of residue pairs. Our comprehensive assessment on the Escherichia coli (E. coli) test dataset showed that HDIContact outperformed other state-of-the-art methods, with top precision of 65.96%, the Area Under the Receiver Operating Characteristic curve (AUROC) of 83.08% and the Area Under the Precision Recall curve (AUPR) of 25.02%. In addition, we analyzed the potential of HDIContact for human-virus protein-protein complexes, by achieving top five precision of 80% on O75475-P04584 related to Human Immunodeficiency Virus. All experiments indicated that our method was a valuable technical tool for predicting inter-protein residue contacts, which would be helpful for understanding protein-protein interaction mechanisms., (© The Author(s) 2022. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.)

Motivation: Coenzyme A (CoA)-protein binding plays an important role in various cellular functions and metabolic pathways. However, no computational methods can be employed for CoA-binding residues prediction., Results: We developed three methods for the prediction of CoA- and CoA derivatives-binding residues, including an ab initio method SVMpred, a template-based method TemPred and a consensus-based method CoABind. In SVMpred, a comprehensive set of features are designed from two complementary sequence profiles and the predicted secondary structure and solvent accessibility. The engine for classification in SVMpred is selected as the support vector machine. For TemPred, the prediction is transferred from homologous templates in the training set, which are detected by the program HHsearch. The assessment on an independent test set consisting of 73 proteins shows that SVMpred and TemPred achieve Matthews correlation coefficient (MCC) of 0.438 and 0.481, respectively. Analysis on the predictions by SVMpred and TemPred shows that these two methods are complementary to each other. Therefore, we combined them together, forming the third method CoABind, which further improves the MCC to 0.489 on the same set. Experiments demonstrate that the proposed methods significantly outperform the state-of-the-art general-purpose ligand-binding residues prediction algorithm COACH. As the first-of-its-kind method, we anticipate CoABind to be helpful for studying CoA-protein interaction., Availability and Implementation: http://yanglab.nankai.edu.cn/CoABind., Supplementary Information: Supplementary data are available at Bioinformatics online.

In recent years, protein structure problems have become a hotspot for understanding protein folding and function mechanisms. It has been observed that most of the protein structure works rely on and benefit from co-evolutionary information obtained by multiple sequence alignment (MSA). As an example, AlphaFold2 (AF2) is a typical MSA-based protein structure tool which is famous for its high accuracy. As a consequence, these MSA-based methods are limited by the quality of the MSAs. Especially for orphan proteins that have no homologous sequence, AlphaFold2 performs unsatisfactorily as MSA depth decreases, which may pose a barrier to its widespread application in protein mutation and design problems in which there are no rich homologous sequences and rapid prediction is needed. In this paper, we constructed two standard datasets for orphan and de novo proteins which have insufficient/none homology information, called Orphan62 and Design204, respectively, to fairly evaluate the performance of the various methods in this case. Then, depending on whether or not utilizing scarce MSA information, we summarized two approaches, MSA-enhanced and MSA-free methods, to effectively solve the issue without sufficient MSAs. MSA-enhanced model aims to improve poor MSA quality from the data source by knowledge distillation and generation models. MSA-free model directly learns the relationship between residues on enormous protein sequences from pre-trained models, bypassing the step of extracting the residue pair representation from MSA. Next, we evaluated the performance of four MSA-free methods (trRosettaX-Single, TRFold, ESMFold and ProtT5) and MSA-enhanced (Bagging MSA) method compared with a traditional MSA-based method AlphaFold2, in two protein structure-related prediction tasks, respectively. Comparison analyses show that trRosettaX-Single and ESMFold which belong to MSA-free method can achieve fast prediction (⁠|$\sim\! 40$| s) and comparable performance compared with AF2 in tertiary structure prediction, especially for short peptides, |$\alpha $| -helical segments and targets with few homologous sequences. Bagging MSA utilizing MSA enhancement improves the accuracy of our trained base model which is an MSA-based method when poor homology information exists in secondary structure prediction. Our study provides biologists an insight of how to select rapid and appropriate prediction tools for enzyme engineering and peptide drug development. Contact guofei@csu.edu.cn , jj.tang@siat.ac.cn [ABSTRACT FROM AUTHOR]

Diseases caused by bacterial infections become a critical problem in public heath. Antibiotic, the traditional treatment, gradually loses their effectiveness due to the resistance. Meanwhile, antibacterial proteins attract more attention because of broad spectrum and little harm to host cells. Therefore, exploring new effective antibacterial proteins is urgent and necessary. In this paper, we are committed to evaluating the effectiveness of ab-initio docking methods in antibacterial protein–protein docking. For this purpose, we constructed a three-dimensional (3D) structure dataset of antibacterial protein complex, called APCset, which contained |$19$| protein complexes whose receptors or ligands are homologous to antibacterial peptides from Antimicrobial Peptide Database. Then we selected five representative ab-initio protein–protein docking tools including ZDOCK3.0.2, FRODOCK3.0, ATTRACT, PatchDock and Rosetta to identify these complexes' structure, whose performance differences were obtained by analyzing from five aspects, including top/best pose, first hit, success rate, average hit count and running time. Finally, according to different requirements, we assessed and recommended relatively efficient protein–protein docking tools. In terms of computational efficiency and performance, ZDOCK was more suitable as preferred computational tool, with average running time of |$6.144$| minutes, average Fnat of best pose of |$0.953$| and average rank of best pose of |$4.158$|⁠. Meanwhile, ZDOCK still yielded better performance on Benchmark 5.0, which proved ZDOCK was effective in performing docking on large-scale dataset. Our survey can offer insights into the research on the treatment of bacterial infections by utilizing the appropriate docking methods. [ABSTRACT FROM AUTHOR]