gmx_RRCS: a precision tool for detecting subtle conformational dynamics in molecular simulations.

Abstract

Understanding conformational changes in biomolecules is crucial for insights into their biological functions and drug design, often studied by molecular dynamics (MD) simulations. However, current measurements such as RMSD, RMSF, interface area, and minimum distances fail to capture subtle conformational changes, including hydrophobic packing. Our study introduces gmx_RRCS, a precision tool developed to detect subtle conformational dynamics in MD simulations by analyzing residue-residue contact scores (RRCS). This tool quantifies interaction strengths between residues, enabling systematic analysis of both major and subtle conformational changes. Its application in investigating the molecular recognition of peptide 20 by glucagon-like peptide-1 receptor quantified the interactions of specific peptide moieties with the receptor, identified crucial positions for receptor binding, and highlighted key receptor residues involved in peptide recognition throughout the MD simulation. In phosphoinositide 3-kinase alpha (PI3Kα), gmx_RRCS revealed distinct conformational states of oncogenic hotspot residues by quantifying subtle sidechain reorientations and salt bridge dynamics. Similarly, in nucleic acid systems, the tool distinguished differential binding mechanisms between ochratoxin A and norfloxacin by revealing unique interaction patterns at critical nucleobases correlating with binding affinities. The tool has been validated through the analysis of over 150 simulation trajectories, covering 40,000 ns of total simulation time and 20 systems. gmx_RRCS significantly advances structural/molecular biology studies by enhancing our understanding of protein conformational dynamics, thereby facilitating rational drug design. gmx_RRCS is freely available on GitHub (https://github.com/RuijinHospitalRCMSB/gmx_RRCS) and PyPI (https://pypi.org/project/gmx-RRCS).