(294b) Ligand Modulated Conformational Landscape of G-Protein Coupled Receptors

G-protein coupled receptors (GPCRs) are membrane proteins that modulate many important biological signal cascades, and are the targets of approximately 40% of all commercially available drugs. Besides binding G proteins, activated β₂AR can be phosphorylated and bind arrestin, which redirects signaling to other pathways. The crystal structures of GPCR’s reveal the structural differences between the active and inactive states but do not give insights into the activation mechanism or pathway relating the active and inactive states. An understanding of GPCR activation mechanism may facilitate the development of more selective drugs with improved therapeutic activity and minimal undesirable side effects. Recent simulation studies (Dror et. al., PNAS, 108, 46, 18684, 2011) have reported a deactivation pathway for β₂AR. However, a more detailed and complete picture of the GPCR conformational landscape is desired. Furthermore, the conformational landscape of the apo-receptor changes due to binding of ligands (confirmed by the NMR spectroscopy results (Liu et. al., Science, 335, 1055, 2012)). Here, we report results from extensive molecular dynamics (MD) simulations of the apo and ligand bound β₂adrenergic receptor(β₂AR) to elucidate the activation and deactivation mechanism of GPCRs and to identify the ligand induced conformational changes in the landscape.