Dynamics of the Internal Water Molecules in Squid Rhodopsin

Abstract

G-protein coupled receptors (GPCRs) are major parmaceutical targets because of their key role in a diverse array of physiological functions. The visual rhodopsin is the prototype for the family A of GPCRs. Upon photoisomerization of the covalently-bound retinal chromophore, visual rhodopsins undergo a large-scale conformational change that prepares the receptor for a productive interaction with the G protein. The mechanism by which the local perturbation of the retinal cis-trans isomerization is transmitted throughout the protein is not well understood. The recently reported crystal structure of squid rhodopsin (M. Murakami and T. Kouyama, Nature 453, 363, 2008) displays new features that may provide additional insight into the mechanism of the signal transduction in GPCRs. It has been suggested, based on the location of water molecules in the interhelical region extending from the retinal towards the cytoplasmic side, that a water-mediated hydrogen-bond network may play a role in the activation process. As a first step towards understanding the role of water in rhodopsin function, we have performed a molecular dynamics simulation of squid rhodopsin embedded in a hydrated bilayer of polyunsaturated lipid molecules. Here we report results from the simulation that show that the water molecules present in the crystal structure participate in favorable interactions with side chains in the interhelical region, and form a persistent hydrogen-bond network in connecting Tyr315 to Trp274 via Asp80. We also present preliminary results from a simulation study of the changes in the structure and dynamics of the hydrogen-bond network that accompany the photoisomerization of the retinal chromophore.