Analysis of protein-protein interface with incorporating low-frequency molecular interactions in molecular dynamics simulation

Abstract

Protein-protein interactions are vital for various biological processes such as immune reaction, signal transduction, and viral infection. Molecular Dynamics (MD) simulation is a powerful tool for analyzing non-covalent interactions between two protein molecules. In general, MD simulation studies on the protein-protein interface have focused on the analysis of major and frequent molecular interactions. In this study, we demonstrate that minor interactions with low-frequency need to be incorporated to analyze the molecular interactions in the protein-protein interface more efficiently using the complex of SARS-CoV2-RBD and ACE2 receptor as a model system. It was observed that the dominance of interactions in the MD-simulated structures didn't directly correlate with the interactions in the experimentally determined structure. The interactions from the experimentally determined structure could be reproduced better in the ensemble of MD simulated structures by including the less frequent interactions compared to the norm of choosing only highly frequent interactions. Residue Interaction Networks (RINs) analysis also showed that the critical residues in the protein-protein interface could be more efficiently identified by incorporating low-frequency interactions in MD simulation. It is expected that the approach proposed in this study can be a new way of studying protein-protein interaction through MD simulation.