GGL-PPI: Geometric Graph Learning to Predict Mutation-Induced Binding Free Energy Changes

원문 초록

Protein-protein interactions (PPIs) are critical for various biological processes, and understanding their dynamics is essential for decoding molecular mechanisms and advancing fields such as cancer research and drug discovery. Mutations in PPIs can disrupt protein binding affinity and lead to functional changes and disease. Predicting the impact of mutations on binding affinity is valuable but experimentally challenging. Computational methods, including physics-based and machine learning-based approaches, have been developed to address this challenge. Machine learning-based methods, fueled by extensive PPI datasets such as Ab-Bind, PINT, SKEMPI, and others, have shown promise in predicting binding affinity changes. However, accurate predictions and generalization of these models across different datasets remain challenging. Geometric graph learning has emerged as a powerful approach, combining graph theory and machine learning, to capture structural features of biomolecules. We present GGL-PPI, a novel method that integrates geometric graph learning and machine learning to predict mutation-induced binding free energy changes. GGL-PPI leverages atom-level graph coloring and multi-scale weighted colored geometric subgraphs to extract informative features, demonstrating superior performance on three validation datasets, namely AB-Bind, SKEMPI 1.0, and SKEMPI 2.0 datasets. Evaluation on a blind test set highlights the unbiased predictions of GGL-PPI for both direct and reverse mutations. The findings underscore the potential of GGL-PPI in accurately predicting binding free energy changes, contributing to our understanding of PPIs and aiding drug design efforts.