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1. E(3) equivariant graph neural networks for robust and accurate protein-protein interaction site prediction

   https://doi.org/10.1371/journal.pcbi.1011435  

   Roche, Rahmatullah; Moussad, Bernard; Shuvo, Md Hossain; Bhattacharya, Debswapna (August 2023, PLOS Computational Biology)

   Li, Jinyan (Ed.)

   Artificial intelligence-powered protein structure prediction methods have led to a paradigm-shift in computational structural biology, yet contemporary approaches for predicting the interfacial residues (i.e., sites) of protein-protein interaction (PPI) still rely on experimental structures. Recent studies have demonstrated benefits of employing graph convolution for PPI site prediction, but ignore symmetries naturally occurring in 3-dimensional space and act only on experimental coordinates. Here we present EquiPPIS, an E(3) equivariant graph neural network approach for PPI site prediction. EquiPPIS employs symmetry-aware graph convolutions that transform equivariantly with translation, rotation, and reflection in 3D space, providing richer representations for molecular data compared to invariant convolutions. EquiPPIS substantially outperforms state-of-the-art approaches based on the same experimental input, and exhibits remarkable robustness by attaining better accuracy with predicted structural models from AlphaFold2 than what existing methods can achieve even with experimental structures. Freely available athttps://github.com/Bhattacharya-Lab/EquiPPIS, EquiPPIS enables accurate PPI site prediction at scale. 

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2. Protein-Nucleic Acid Complex Modeling with Frame Averaging Transformer

   Huang, T; Song, Z; Ying, R; Jin, W (December 2024, Neural Information Processing Systems)

   Nucleic acid-based drugs like aptamers have recently demonstrated great therapeutic potential. However, experimental platforms for aptamer screening are costly, and the scarcity of labeled data presents a challenge for supervised methods to learn protein-aptamer binding. To this end, we develop an unsupervised learning approach based on the predicted pairwise contact map between a protein and a nucleic acid and demonstrate its effectiveness in protein-aptamer binding prediction. Our model is based on FAFormer, a novel equivariant transformer architecture that seamlessly integrates frame averaging (FA) within each transformer block. This integration allows our model to infuse geometric information into node features while preserving the spatial semantics of coordinates, leading to greater expressive power than standard FA models. Our results show that FAFormer outperforms existing equivariant models in contact map prediction across three protein complex datasets, with over 10% relative improvement. Moreover, we curate five real-world protein-aptamer interaction datasets and show that the contact map predicted by FAFormer serves as a strong binding indicator for aptamer screening. 

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3. Twenty years of advances in prediction of nucleic acid-binding residues in protein sequences

   https://doi.org/10.1093/bib/bbaf016  

   Basu, Sushmita; Yu, Jing; Kihara, Daisuke; Kurgan, Lukasz (January 2025, Briefings in Bioinformatics)

   Abstract Computational prediction of nucleic acid-binding residues in protein sequences is an active field of research, with over 80 methods that were released in the past 2 decades. We identify and discuss 87 sequence-based predictors that include dozens of recently published methods that are surveyed for the first time. We overview historical progress and examine multiple practical issues that include availability and impact of predictors, key features of their predictive models, and important aspects related to their training and assessment. We observe that the past decade has brought increased use of deep neural networks and protein language models, which contributed to substantial gains in the predictive performance. We also highlight advancements in vital and challenging issues that include cross-predictions between deoxyribonucleic acid (DNA)-binding and ribonucleic acid (RNA)-binding residues and targeting the two distinct sources of binding annotations, structure-based versus intrinsic disorder-based. The methods trained on the structure-annotated interactions tend to perform poorly on the disorder-annotated binding and vice versa, with only a few methods that target and perform well across both annotation types. The cross-predictions are a significant problem, with some predictors of DNA-binding or RNA-binding residues indiscriminately predicting interactions with both nucleic acid types. Moreover, we show that methods with web servers are cited substantially more than tools without implementation or with no longer working implementations, motivating the development and long-term maintenance of the web servers. We close by discussing future research directions that aim to drive further progress in this area. 

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4. Geometry-complete perceptron networks for 3D molecular graphs

   https://doi.org/10.1093/bioinformatics/btae087  

   Morehead, Alex; Cheng, Jianlin; Valencia, ed., Alfonso (February 2024, Bioinformatics)

   Abstract MotivationThe field of geometric deep learning has recently had a profound impact on several scientific domains such as protein structure prediction and design, leading to methodological advancements within and outside of the realm of traditional machine learning. Within this spirit, in this work, we introduce GCPNet, a new chirality-aware SE(3)-equivariant graph neural network designed for representation learning of 3D biomolecular graphs. We show that GCPNet, unlike previous representation learning methods for 3D biomolecules, is widely applicable to a variety of invariant or equivariant node-level, edge-level, and graph-level tasks on biomolecular structures while being able to (1) learn important chiral properties of 3D molecules and (2) detect external force fields. ResultsAcross four distinct molecular-geometric tasks, we demonstrate that GCPNet’s predictions (1) for protein–ligand binding affinity achieve a statistically significant correlation of 0.608, more than 5%, greater than current state-of-the-art methods; (2) for protein structure ranking achieve statistically significant target-local and dataset-global correlations of 0.616 and 0.871, respectively; (3) for Newtownian many-body systems modeling achieve a task-averaged mean squared error less than 0.01, more than 15% better than current methods; and (4) for molecular chirality recognition achieve a state-of-the-art prediction accuracy of 98.7%, better than any other machine learning method to date. Availability and implementationThe source code, data, and instructions to train new models or reproduce our results are freely available at https://github.com/BioinfoMachineLearning/GCPNet. 

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5. 3D-equivariant graph neural networks for protein model quality assessment

   https://doi.org/10.1093/bioinformatics/btad030  

   Chen, Chen; Chen, Xiao; Morehead, Alex; Wu, Tianqi; Cheng, Jianlin; Cowen, ed., Lenore (January 2023, Bioinformatics)

   Abstract MotivationQuality assessment (QA) of predicted protein tertiary structure models plays an important role in ranking and using them. With the recent development of deep learning end-to-end protein structure prediction techniques for generating highly confident tertiary structures for most proteins, it is important to explore corresponding QA strategies to evaluate and select the structural models predicted by them since these models have better quality and different properties than the models predicted by traditional tertiary structure prediction methods. ResultsWe develop EnQA, a novel graph-based 3D-equivariant neural network method that is equivariant to rotation and translation of 3D objects to estimate the accuracy of protein structural models by leveraging the structural features acquired from the state-of-the-art tertiary structure prediction method—AlphaFold2. We train and test the method on both traditional model datasets (e.g. the datasets of the Critical Assessment of Techniques for Protein Structure Prediction) and a new dataset of high-quality structural models predicted only by AlphaFold2 for the proteins whose experimental structures were released recently. Our approach achieves state-of-the-art performance on protein structural models predicted by both traditional protein structure prediction methods and the latest end-to-end deep learning method—AlphaFold2. It performs even better than the model QA scores provided by AlphaFold2 itself. The results illustrate that the 3D-equivariant graph neural network is a promising approach to the evaluation of protein structural models. Integrating AlphaFold2 features with other complementary sequence and structural features is important for improving protein model QA. Availability and implementationThe source code is available at https://github.com/BioinfoMachineLearning/EnQA. Supplementary informationSupplementary data are available at Bioinformatics online. 

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