Geometric Graph Learning to Predict Changes in Binding Free Energy and Protein Thermodynamic Stability upon Mutation
Md Masud Rana, Duc Duy Nguyen
Abstract
Accurate prediction of binding free energy changes upon mutations is vital for optimizing drugs, designing proteins, understanding genetic diseases, and cost-effective virtual screening. While machine learning methods show promise in this domain, achieving accuracy and generalization across diverse data sets remains a challenge. This study introduces Geometric Graph Learning for Protein-Protein Interactions (GGL-PPI), a novel approach integrating geometric graph representation and machine learning to forecast mutation-induced binding free energy changes. GGL-PPI leverages atom-level graph coloring and multiscale weighted colored geometric subgraphs to capture structural features of biomolecules, demonstrating superior performance on three standard data sets, namely, AB-Bind, SKEMPI 1.0, and SKEMPI 2.0 data sets. The model's efficacy extends to predicting protein thermodynamic stability in a blind test set, providing unbiased predictions for both direct and reverse mutations and showcasing notable generalization. GGL-PPI's precision in predicting changes in binding free energy and stability due to mutations enhances our comprehension of protein complexes, offering valuable insights for drug design endeavors.