Hom-Complex-Based Machine Learning (HCML) for the Prediction of Protein–Protein Binding Affinity Changes upon Mutation

• Published in: Journal of chemical information and modeling Vol. 62; no. 17; pp. 3961 - 3969
• Main Authors: Liu, Xiang, Feng, Huitao, Wu, Jie, Xia, Kelin
• Format: Journal Article
• Language: English
• Published: Washington American Chemical Society 12.09.2022
• Subjects: Affinity; Antibodies; Artificial intelligence; Binding; Biological activity; Graph representations; Graphical representations; Homology; Machine learning; Machine Learning and Deep Learning; Mutation; Proteins; Severe acute respiratory syndrome coronavirus 2
• ISSN: 1549-9596; 1549-960X
• DOI: 10.1021/acs.jcim.2c00580

Protein–protein interactions (PPIs) are involved in almost all biological processes in the cell. Understanding protein–protein interactions holds the key for the understanding of biological functions, diseases and the development of therapeutics. Recently, artificial intelligence (AI) models have demonstrated great power in PPIs. However, a key issue for all AI-based PPI models is efficient molecular representations and featurization. Here, we propose Hom-complex-based PPI representation, and Hom-complex-based machine learning models for the prediction of PPI binding affinity changes upon mutation, for the first time. In our model, various Hom complexes Hom(G 1, G) can be generated for the graph representation G of protein–protein complex by using different graphs G 1, which reveal G 1-related inner connections within the graph representation G of protein–protein complex. Further, for a specific graph G 1, a series of nested Hom complexes are generated to give a multiscale characterization of the PPIs. Its persistent homology and persistent Euler characteristic are used as molecular descriptors and further combined with the machine learning model, in particular, gradient boosting tree (GBT). We systematically test our model on the two most-commonly used data sets, that is, SKEMPI and AB-Bind. It has been found that our model outperforms all the existing models as far as we know, which demonstrates the great potential of our model for the analysis of PPIs. Our model can be used for the analysis and design of efficient antibodies for SARS-CoV-2.