Roughly one-third of all drugs act by binding to G-protein-coupled receptors (GPCRs) and either triggering or preventing receptor activation.  The process by which they do so has proven difficult to determine, however, despite dramatic recent advances in GPCR crystallography.  We have performed atomic-level molecular dynamics simulations in which drugs spontaneously associate with GPCRs to achieve bound conformations that match crystal structures almost perfectly.  We have used such simulations not only to characterize the drug binding process but also to capture the structural basis for modulation of a GPCR by allosteric drugs.  Our simulations also capture spontaneous transitions of GPCRs and G proteins between various conformational states, allowing us to characterize the mechanism of GPCR activation and the mechanism by which a GPCR activates a G protein.  Our results, together with complementary experimental data, suggest opportunities for the design of drugs that achieve greater specificity and control receptor signaling more precisely.<br/>

Revealing the structural basis for GPCR signaling through atomic-level simulation

254th National Meeting (2017)

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