Predicting single mutation effects on binding affinity at protein-protein interfaces based on MMPBSA calculations

Abstract

Accurate prediction of mutation-induced changes in protein-protein affinity remains a central challenge in computational biophysics and protein engineering. Here we present a physics-based scoring method for predicting the effects of single amino acid substitutions on protein-protein and protein-peptide binding affinity. The method is based on MMPBSA energy calculations and implemented in a user-friendly, publicly available workflow (https://github.com/Hoecker-Lab/mmpbsa_scoring). To derive the scoring function, MMPBSA energy terms were fitted using a large and diverse dataset of experimentally measured binding affinity changes upon point mutation. The terms were then evaluated on independent systems. Specifically, we assessed the ability to predict mutational effects at the interface of SARS-CoV-2 spike protein with its cellular receptor, as well as computationally predicted Armadillo-repeat protein-peptide complexes. The approach performs well across diverse targets and shows promising predictive performance on both experimentally determined and computationally predicted structures. It matches or exceeds the accuracy of established physics-based protein design software and state-of-the-art deep learning-based scoring functions when applied to data outside their training domain. The method provides a computationally efficient and interpretable framework for prioritizing interface mutations in protein engineering and binding affinity optimization.