title: Investigation of the conformational dynamics of the apo A2A adenosine receptor.
abstract: The activation/deactivation processes for G-protein coupled receptors (GPCRs) have been computationally studied for several different classes, including rhodopsin, the β2 adrenergic receptor, and the M2 muscarinic receptor. Despite determined cocrystal structures of the adenosine A2A receptor (A2A AR) in complex with antagonists, agonists and an antibody, the deactivation process of this GPCR is not completely understood. In this study, we investigate the convergence of two apo simulations, one starting with an agonist-bound conformation (PDB: 3QAK)(14) and the other starting with an antagonist-bound conformation (PDB: 3EML)(11) . Despite the two simulations not completely converging, we were able to identify distinct intermediate steps of the deactivation process characterized by the movement of Y288(7.53) in the NPxxY motif. We find that Y288(7.53) contributes to the process by forming hydrogen bonds to residues in transmembrane helices 2 and 7 and losing these interactions upon full deactivation. Y197(5.58) also plays a role in the process by forming a hydrogen bond only once the side chain moves from the lipid interface to the middle of the helical bundle.
authors.affiliation: Department of Pharmacology, University of California at San Diego, La Jolla, California, 92093.
authors.forename: Alisha D
authors.initials: AD
authors.lastname: Caliman
authors.affiliation: Department of Pharmacology, University of California at San Diego, La Jolla, California, 92093.
authors.forename: Sara E
authors.initials: SE
authors.lastname: Swift
authors.affiliation: Howard Hughes Medical Institute, University of California at San Diego, La Jolla, California, 92093.
authors.forename: Yi
authors.initials: Y
authors.lastname: Wang
authors.affiliation: Howard Hughes Medical Institute, University of California at San Diego, La Jolla, California, 92093.
authors.forename: Yinglong
authors.initials: Y
authors.lastname: Miao
authors.affiliation: Department of Pharmacology, University of California at San Diego, La Jolla, California, 92093.|Howard Hughes Medical Institute, University of California at San Diego, La Jolla, California, 92093.|Department of Chemistry and Biochemistry, University of California at San Diego, La Jolla, California, 92093.
authors.forename: J Andrew
authors.initials: JA
authors.lastname: McCammon
mesh_terms: D003198:Computer Simulation; D006801:Humans; D006860:Hydrogen Bonding; D056004:Molecular Dynamics Simulation; D011487:Protein Conformation; D043705:Receptor, Adenosine A2A / Q000737:chemistry* / Q000378:metabolism*
chemical_list: D043705:Receptor, Adenosine A2A
keywords: GPCR; NPxxY; activation; adenosine A2A; molecular dynamics