A Microsecond Time Scale Molecular Dynamics Simulation of B2AR in a Membrane

Abstract

We present the results of a 1 microsecond all-atom molecular dynamics simulation of a B2AR monomer embedded in a lipid bilayer. The initial model was derived from the crystal structure of the carazolol-bound B2AR-T4 lysozyme fusion protein (Rosenbaum et al, Science 2007 318:1266-73), where the T4-lysozyme and carazolol ligand were removed. Singular value decomposition and CA-RMSD analyses show a remarkably stable structure with three large-scale conformational substates. The majority of motions associated with these states occur at the ends of the transmembrane helices. The protein core, and in particular, the key structural/functional regions around the highly conserved proline residues of TM5, TM6, and TM7 remain very stable. Water rapidly infiltrates the protein core, forming pockets that are persistently hydrated, including the ligand binding pocket. Remarkably, the distorted Pro-kink in TM6 is stabilized by individual water molecules with very long residence times; the simulation is able to perfectly mimic this feature that is observed in the crystal structures of bovine and squid rhodopsin and in B1AR and B2AR, and is probably common of other class A GPCRs.