Advances in enhanced sampling simulations of G-protein-coupled receptors

Abstract

G-protein-coupled receptors (GPCRs) constitute the largest family of membrane proteins involved in cellular signaling. Although X-ray crystallography and cryo-Electron Microscopy (cryo-EM) have provided valuable structural insights into GPCRs, these experimental techniques primarily capture static conformations and cannot fully resolve the dynamic transitions that underlie activation, allostery, ligand recognition, and signaling of GPCRs. In this perspective, we highlight Molecular Dynamics (MD) simulations of GPCRs using enhanced sampling methods. These computational approaches have provided mechanistic insights into receptor activation and deactivation mechanisms, allosteric communication networks, ligand and peptide binding and dissociation pathways, and GPCR–G protein interaction kinetics while revealing transient intermediate states that are often inaccessible to experiments. Together, these advances provide a powerful framework for understanding GPCR signaling mechanisms and accelerating the rational design of selective therapeutics with improved efficacy and reduced side effects.