Dynamic Ligand-Protein Interactions Alter Rhodopsin's Conformational Ensemble: Simulations of Rhodopsin and Opsin

Abstract

Given their function as transducers of molecular signals across the cell membrane, G protein-coupled receptors (GPCRs) constitute a major target for drugs in a wide variety of physiological scenarios. Understanding the course of structural transitions that allosterically modulate their activation is, therefore, fundamental towards improving rational drug design. Here, we characterize distinct ensembles of all- atom molecular dynamics simulations of class A GPCR, rhodopsin. These ensembles correspond to the active- and inactive-like form of the receptor, with and without ligand, and amount to an aggregate sampling time of ∼116 μs. By monitoring ligand orientation within the binding pocket, we observe that retinal adopts diverse, heterogeneous conformations that are consistent with ensemble-dependent dynamics. We also investigate internal hydration within the four ensembles and note how variations in solvation within the core and ligand dynamics may modulate the activity of the receptor.