Decoding Protein–Membrane Binding Interfaces from Surface-Fingerprint-Based Geometric Deep Learning and Molecular Dynamics Simulations

Predicting protein-membrane interactions is a formidable challenge due to the subtle physicochemical features that distinguish membrane-binding regions of a protein surface as well as the scarcity of experimentally resolved membrane-bound protein conformations. Here, we present MaSIF-PMP, a geometric deep learning model that leverages molecular surface fingerprints to predict interfacial binding sites (IBSs) of peripheral membrane proteins (PMPs). MaSIF-PMP integrates geometric and chemical surface features to produce spatially resolved IBS predictions. Compared to existing models, MaSIF-PMP achieves superior performance for IBS classification, while feature ablation studies and transfer learning analyses reveal distinct determinants governing protein-membrane versus protein-protein interactions. We further show that molecular dynamics (MD) simulations can validate model predictions, refine IBS labels, and capture composition-dependent membrane binding patterns. These results establish MaSIF-PMP as an effective framework for IBS prediction and highlight the potential of incorporating conformational dynamics from MD to improve both the model accuracy and biological interpretability.