Modeling the impact of amino acid mutations on protein-protein interaction plays a crucial role in protein engineering and drug design. In this study, we develop GeoPPI, a novel structure-based deep-learning framework to predict the change of binding affinity upon mutations. Based on the three-dimensional structure of a protein, GeoPPI first learns a geometric representation that encodes topology features of the protein structure via a self-supervised learning scheme. These representations are then used as features for training gradient-boosting trees to predict the changes of protein-protein binding affinity upon mutations. We find that GeoPPI is able to learn meaningful features that characterize interactions between atoms in protein structures. In addition, through extensive experiments, we show that GeoPPI achieves new state-of-the-art performance in predicting the binding affinity changes upon both single- and multi-point mutations on six benchmark datasets. Moreover, we show that GeoPPI can accurately estimate the difference of binding affinities between a few recently identified SARS-CoV-2 antibodies and the receptor-binding domain (RBD) of the S protein. These results demonstrate the potential of GeoPPI as a powerful and useful computational tool in protein design and engineering. Our code and datasets are available at: https://github.com/Liuxg16/GeoPPI . Author summary Estimating the binding affinities of protein-protein interactions (PPIs) is crucial to understand protein function and design new functional proteins. Since the experimental measurement in wet-labs is labor-intensive and time-consuming, fast and accurate in silico approaches have received much attention. Although considerable efforts have been made in this direction, predicting the effects of mutations on the protein-protein binding affinity is still a challenging research problem. In this work, we introduce GeoPPI, a novel computational approach that uses deep geometric representations of protein complexes to predict the effects of mutations on the binding affinity. The geometric representations are first learned via a self-supervised learning scheme and then integrated with gradient-boosting trees to accomplish the prediction. We find that the learned representations encode meaningful patterns underlying the interactions between atoms in protein structures. Also, extensive tests on major benchmark datasets show that GeoPPI has made an important improvement over the existing methods in predicting the effects of mutations on the binding affinity.
【초록키워드】 Mutation, drug design, mutations, Proteins, binding affinity, Protein, SARS-CoV-2 antibody, RBD, Protein design, modeling, Research, dataset, change, predict, protein-protein interaction, Amino acid, Interaction, structures, in silico Approach, three-dimensional structure, effort, datasets, protein complex, Topology, ENCODE, Effect, approach, feature, develop, addition, functional, the receptor-binding domain, the S protein, experiments, the binding affinity, time-consuming, geometric, labor-intensive, 【제목키워드】 Mutation, binding affinity, Effect, deep, geometric,