Atomic Level Description of GPCR Activation Revealed by Microsecond Time Scale Molecular Dynamics

Abstract

Previously, we had reported the results of microsecond molecular dynamics simulations for the interaction of 2-arachidonoylglycerol (2AG), the endogenous ligand of the Class A cannabinoid CB2 receptor, with the CB2 receptor in an explicit POPC lipid bilayer[1]. These results show the initial stages of agonist binding to and activation of the CB2 receptor. Analysis of these trajectories reveals that upon the binding of 2AG, which occurs via lipid between transmembrane helix 6 (TMH6) and TMH7, the intracellular portions of TMH3 and 6 separate with a concurrent breaking of an intracellular salt bridge. The latter event has been probed by an Essential Dynamics analysis of the trajectory during the binding event. This analysis indicates that a single eigenvector captures the motion of the breaking of this salt bridge and the opening of the intracellular surface of the receptor, events that are believed to be associated with activation. These results will be presented and discussed, particularly in light of recent experimental results of spin label measurements by Altenbach et al. [2] and the crystal structures of opsin [3,4] which both show an intracellular separation of between 6-7 A between the ends of TMH3/TMH6 of rhodopsin upon light activation.[1] Reggio, P. et al. Biophys. Supplement 94, 2676 (2008).[2] Altenbach, C. et al. PNAS, 105, 7439-7444 (2008).[3] Park, J.H. et al. Nature 454, 183-187 (2008).[4] Scheerer, P. et al. Nature 455, 497-502 (2008).