Investigation of the conformational dynamics of the apo A2A adenosine receptor

• Published in: Protein science 2015-06, Vol.24 (6), p.1004-1012
• Main Authors: Caliman, Alisha D., Swift, Sara E., Wang, Yi, Miao, Yinglong, McCammon, J. Andrew
• Format: Article
• Language: English
• Subjects: activation; Adenosine; adenosine A2A; Computer Simulation; GPCR; Humans; Hydrogen Bonding; Hydrogen bonds; molecular dynamics; Molecular Dynamics Simulation; NPxxY; Protein Conformation; Receptor, Adenosine A2A - chemistry; Receptor, Adenosine A2A - metabolism
• ISSN: 0961-8368; 1469-896X
• DOI: 10.1002/pro.2681

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 (A2AAR) 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 Y2887.53 in the NPxxY motif. We find that Y2887.53 contributes to the process by forming hydrogen bonds to residues in transmembrane helices 2 and 7 and losing these interactions upon full deactivation. Y1975.58 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.