G-protein-coupled receptors (GPCRs) represent primary targets of about one third of currently marketed drugs. The structure, dynamics and function of GPCRs result from complex free energy landscapes. In this work, we have performed all-atom enhanced simulations using the robust Gaussian accelerated molecular dynamics (GaMD) method to investigate the ligand-dependent structural dynamics of the M<sub>2</sub> muscarinic GPCR. Extensive GaMD simulations have revealed distinct structural flexibility and free energy profiles that depict graded activation of the M<sub>2</sub> receptor. Both dissociation and binding of an orthosteric ligand have been unprecedentedly captured in a single all-atom GPCR simulation. This study demonstrates the applicability of GaMD for exploring free energy landscapes of large biomolecules and the simulations provide important insights into GPCR functional mechanism. GaMD is well poised to study large biomolecules and ligand recognition for drug discovery.

Graded activation and free energy landscapes of a muscarinic G protein-coupled receptor

253rd National Meeting (2017)

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