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(102) ps to ∼O(102) ns. Especially, water molecules, exhibiting ultraslow relaxation (∼O(102) 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.
Bibliographical noteFunding Information:
This work was supported by grant No. 2011-0028885 from the National Leading Research Laboratory program, funded by the Ministry of Science, ICT & Future Planning and the National Research Foundation of Korea (to S.C.), and by RP-Grant 2015 funded by Ewha Womans University (to S.C. and Y.L.).
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