G-protein-coupled receptors (GPCRs) are allosteric signaling machines that trigger distinct functional responses depending on the particular conformational state they adopt upon binding. This so-called GPCR functional selectivity is prompted by ligands of different efficacy binding at orthosteric or allosteric sites on the receptor, as well as by interactions with intracellular protein partners or other receptor types. Molecular dynamics (MD) simulations can provide important mechanistic, thermodynamic, and kinetic insights into these interactions at a level of molecular detail that is necessary to rightly inform modern drug discovery. Here, we review the most recent MD contributions to understanding GPCR allostery, with an emphasis on their strengths and limitations.
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