Significance 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 applied Gaussian accelerated molecular dynamics (GaMD) to study the ligand-dependent behavior of the M 2 muscarinic GPCR. Extensive GaMD simulations have revealed distinct structural flexibility and free energy profiles that depict graded activation of the M 2 receptor. We have captured both dissociation and binding of an orthosteric ligand in a single all-atom GPCR simulation. GaMD is well poised to study large biomolecules and ligand recognition for drug discovery.
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Miao et al. (2016) studied this question.