Kinetics of G Protein-Coupled Receptor Dimerization from Markov State Model Analysis of Coarse-Grained Simulations

Abstract

Experimental and computational studies published over the past decade have mostly focused on the structural and thermodynamic properties of putative G Protein-Coupled Receptor(GPCR) dimers. Although equally crucial for addressing the role of dimerization in GPCR function, a thorough description of the timescales required to form different dimeric interfaces has yet to be provided. In this study, we approach this question by applying Markov State Model analysis to coarse grained simulations of a prototypic GPCR, the mu-opioid receptor (MOR), carried out in a 1-palmitoyl-2-oleoyl-sn-glycero-3-phosphocholine/cholesterol membrane model using an adaptive sampling strategy. We identify several dimerization interfaces of MOR grouped in four macrostates with significantly different dimerization rates, and characterize the role of lipid dynamics, protein-lipid and specific protein-protein interactions in modulating the kinetic properties of receptor dimerization. Furthermore, we discuss the interplay between receptor activation and dimer formation by comparing the results obtained for the activated and inactive receptor conformations of MOR, and observe substantial differences in the dimerization kinetics for the two conformations.