title: Simulations of biased agonists in the β(2) adrenergic receptor with accelerated molecular dynamics.
abstract: The biased agonism of the G protein-coupled receptors (GPCRs), where in addition to a traditional G protein-signaling pathway a GPCR promotes intracellular signals though β-arrestin, is a novel paradigm in pharmacology. Biochemical and biophysical studies have suggested that a GPCR forms a distinct ensemble of conformations signaling through the G protein and β-arrestin. Here we report on the dynamics of the β2 adrenergic receptor bound to the β-arrestin and G protein-biased agonists and the empty receptor to further characterize the receptor conformational changes caused by biased agonists. We use conventional and accelerated molecular dynamics (aMD) simulations to explore the conformational transitions of the GPCR from the active state to the inactive state. We found that aMD simulations enable monitoring of the transition within the nanosecond time scale while capturing the known microscopic characteristics of the inactive states, such as the ionic lock, the inward position of F6.44, and water clusters. Distinct conformational states are shown to be stabilized by each biased agonist. In particular, in simulations of the receptor with the β-arrestin-biased agonist N-cyclopentylbutanepherine, we observe a different pattern of motions in helix 7 when compared to simulations with the G protein-biased agonist salbutamol that involves perturbations of the network of interactions within the NPxxY motif. Understanding the network of interactions induced by biased ligands and the subsequent receptor conformational shifts will lead to development of more efficient drugs.
authors.affiliation: Molecular Therapeutics, School of Pharmacy, Medical Biology Centre, Queen's University, Belfast BT9 7BL, Northern Ireland, UK. i.tikhonova@qub.ac.uk
authors.forename: Irina G
authors.initials: IG
authors.lastname: Tikhonova
authors.forename: Balaji
authors.initials: B
authors.lastname: Selvam
authors.forename: Anthony
authors.initials: A
authors.lastname: Ivetac
authors.forename: Jeff
authors.initials: J
authors.lastname: Wereszczynski
authors.forename: J Andrew
authors.initials: JA
authors.lastname: McCammon
mesh_terms: D058666:Adrenergic beta-2 Receptor Agonists / Q000737:chemistry / Q000378:metabolism; D000420:Albuterol / Q000737:chemistry / Q000378:metabolism; D020816:Amino Acid Motifs; D000595:Amino Acid Sequence; D019390:Arrestins / Q000378:metabolism; D001665:Binding Sites; D018360:Crystallography, X-Ray; D006801:Humans; D006860:Hydrogen Bonding; D007700:Kinetics; D008024:Ligands; D008958:Models, Molecular; D056004:Molecular Dynamics Simulation; D009638:Norepinephrine / Q000031:analogs & derivatives* / Q000737:chemistry / Q000378:metabolism; D025341:Principal Component Analysis; D011487:Protein Conformation; D017433:Protein Structure, Secondary; D017434:Protein Structure, Tertiary; D018343:Receptors, Adrenergic, beta-2 / Q000737:chemistry / Q000378:metabolism*; D043562:Receptors, G-Protein-Coupled / Q000378:metabolism; D013997:Time Factors; D000071557:beta-Arrestins
chemical_list: D058666:Adrenergic beta-2 Receptor Agonists; D019390:Arrestins; D008024:Ligands; D018343:Receptors, Adrenergic, beta-2; D043562:Receptors, G-Protein-Coupled; D000071557:beta-Arrestins; C000542:N-cyclopentylbutanephrine; D000420:Albuterol; D009638:Norepinephrine