title: Ultraslow Water-Mediated Transmembrane Interactions Regulate the Activation of A2A Adenosine Receptor.
abstract: Water molecules inside a G-protein coupled receptor (GPCR) have recently been spotlighted in a series of crystal structures. To decipher the dynamics and functional roles of internal water molecules in GPCR activity, we studied the A2A adenosine receptor using microsecond molecular-dynamics simulations. Our study finds that the amount of water flux across the transmembrane (TM) domain varies depending on the receptor state, and that the water molecules of the TM channel in the active state flow three times more slowly than those in the inactive state. Depending on the location in solvent-protein interface as well as the receptor state, the average residence time of water in each residue varies from ∼O(10(2)) ps to ∼O(10(2)) ns. Especially, water molecules, exhibiting ultraslow relaxation (∼O(10(2)) ns) in the active state, are found around the microswitch residues that are considered activity hotspots for GPCR function. A continuous allosteric network spanning the TM domain, arising from water-mediated contacts, is unique in the active state, underscoring the importance of slow water molecules in the activation of GPCRs.
authors.affiliation: National Leading Research Laboratory of Molecular Modeling and Drug Design, College of Pharmacy and Graduate School of Pharmaceutical Sciences, Ewha Womans University, Seoul, Korea.
authors.forename: Yoonji
authors.initials: Y
authors.lastname: Lee
authors.affiliation: Korea Institute for Advanced Study, Seoul, Korea.
authors.forename: Songmi
authors.initials: S
authors.lastname: Kim
authors.affiliation: National Leading Research Laboratory of Molecular Modeling and Drug Design, College of Pharmacy and Graduate School of Pharmaceutical Sciences, Ewha Womans University, Seoul, Korea. Electronic address: sunchoi@ewha.ac.kr.
authors.forename: Sun
authors.initials: S
authors.lastname: Choi
authors.affiliation: Korea Institute for Advanced Study, Seoul, Korea. Electronic address: hyeoncb@kias.re.kr.
authors.forename: Changbong
authors.initials: C
authors.lastname: Hyeon
mesh_terms: D058908:Adenosine A2 Receptor Agonists / Q000737:chemistry; D058917:Adenosine A2 Receptor Antagonists / Q000737:chemistry; D000494:Allosteric Regulation; D002462:Cell Membrane / Q000737:chemistry; D057927:Hydrophobic and Hydrophilic Interactions; D007700:Kinetics; D056004:Molecular Dynamics Simulation; D011485:Protein Binding; D011487:Protein Conformation; D043705:Receptor, Adenosine A2A / Q000737:chemistry* / Q000235:genetics; D013997:Time Factors; D014867:Water / Q000737:chemistry*
chemical_list: D058908:Adenosine A2 Receptor Agonists; D058917:Adenosine A2 Receptor Antagonists; D043705:Receptor, Adenosine A2A; D014867:Water