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Ultraslow water-mediated transmembrane interactions regulate the activation of A2A adenosine receptor

Yoonji Lee, Songmi Kim, Sun Choi, Changbong Hyeon
doi: https://doi.org/10.1101/067751
Yoonji Lee
1National Leading Research Laboratory (NLRL) of Molecular Modeling and Drug Design, College of Pharmacy and Graduate School of Pharmaceutical Sciences, Ewha Womans University, Seoul 03760, Korea
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Songmi Kim
2Korea Institute for Advanced Study, Seoul 02455, Republic of Korea
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Sun Choi
1National Leading Research Laboratory (NLRL) of Molecular Modeling and Drug Design, College of Pharmacy and Graduate School of Pharmaceutical Sciences, Ewha Womans University, Seoul 03760, Korea
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Changbong Hyeon
2Korea Institute for Advanced Study, Seoul 02455, Republic of Korea
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Abstract

Water molecules inside G-protein coupled receptor have recently been spotlighted in a series of crystal structures. To decipher the dynamics and functional roles of internal waters in GPCR activity, we studied A2A adenosine receptor using μsec-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 slower 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 Embedded Image psec to Embedded Image nsec. Especially, water molecules, exhibiting ultraslow relaxation (Embedded Image nsec) 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 waters in the GPCR activation.

Footnotes

  • ↵* sunchoi{at}ewha.ac.kr

  • ↵† hyeoncb{at}kias.re.kr

Copyright 
The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY-NC-ND 4.0 International license.
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Posted August 04, 2016.
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Ultraslow water-mediated transmembrane interactions regulate the activation of A2A adenosine receptor
Yoonji Lee, Songmi Kim, Sun Choi, Changbong Hyeon
bioRxiv 067751; doi: https://doi.org/10.1101/067751
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Ultraslow water-mediated transmembrane interactions regulate the activation of A2A adenosine receptor
Yoonji Lee, Songmi Kim, Sun Choi, Changbong Hyeon
bioRxiv 067751; doi: https://doi.org/10.1101/067751

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