Chapter 20: Probing the Conformational Dynamics of GPCRs with Molecular Dynamics Simulation

A mounting body of evidence indicates that G-protein–coupled receptors (GPCRs), which represent the largest class of both human membrane proteins and drug targets, can interconvert between numerous conformational states with distinct intracellular signaling profiles. Molecular dynamics (MD) simulation represents a promising method for characterizing these states, their role in signal transduction, and the mechanisms by which drugs and endogenous ligands select among them. Dramatic increases in achievable simulation length and an explosion in the number of available GPCR crystal structures are beginning to remove the major obstacles that have hindered MD simulations of GPCRs in the past. Here, we summarize the factors determining the applicability of MD simulation to the study of GPCR conformational dynamics, provide a brief history of GPCR simulations, and discuss future prospects for using MD to elucidate the dynamical behavior of GPCRs as well as their interactions with ligands and intracellular signaling proteins.