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Title: Ligand-Dependent Sodium Ion Dynamics within the A 2A Adenosine Receptor: A Molecular Dynamics Study

Abstract

Sodium ions have long been known to reduce the binding of agonists in many class-A GPCRs while having little effect on antagonist binding. In this study, using long-time scale classical all-atom molecular dynamics simulations, we explore, in atomic detail, the motion of sodium ions within the ligand-binding pocket of the A 2A adenosine receptor (A2A-AR) both in the presence and absence of ligands and in the active and inactive state. We identify novel secondary ion binding sites within the pocket and find that the types of ion motions within the pocket are highly dependent on the presence and type of ligand within the pocket. Finally, our results provide a first step toward developing a molecular understanding of the impact of sodium ions on class-A GPCRs.

Authors:
 [1]; ORCiD logo [2];  [2];  [2]; ORCiD logo [3]; ORCiD logo [4]; ORCiD logo [2]
  1. Univ. of Tennessee, Knoxville, TN (United States); Icahn School of Medicine at Mount Sinai, New York, NY (United States); Oak Ridge National Lab. (ORNL), Oak Ridge, TN (United States)
  2. Univ. of Tennessee, Knoxville, TN (United States); Oak Ridge National Lab. (ORNL), Oak Ridge, TN (United States)
  3. Oak Ridge National Lab. (ORNL), Oak Ridge, TN (United States)
  4. Univ. of Alabama, Huntsville, AL (United States)
Publication Date:
Research Org.:
Oak Ridge National Lab. (ORNL), Oak Ridge, TN (United States)
Sponsoring Org.:
USDOE
OSTI Identifier:
1561656
Grant/Contract Number:  
AC05-00OR22725
Resource Type:
Accepted Manuscript
Journal Name:
Journal of Physical Chemistry. B, Condensed Matter, Materials, Surfaces, Interfaces and Biophysical Chemistry
Additional Journal Information:
Journal Volume: 123; Journal Issue: 38; Journal ID: ISSN 1520-6106
Publisher:
American Chemical Society
Country of Publication:
United States
Language:
English
Subject:
37 INORGANIC, ORGANIC, PHYSICAL, AND ANALYTICAL CHEMISTRY; 59 BASIC BIOLOGICAL SCIENCES

Citation Formats

Hu, Xiaohu, Smith, Micholas Dean, Humphreys, Bailey M., Green, Adam T., Parks, Jerry M., Baudry, Jerome Y., and Smith, Jeremy C. Ligand-Dependent Sodium Ion Dynamics within the A2A Adenosine Receptor: A Molecular Dynamics Study. United States: N. p., 2019. Web. doi:10.1021/acs.jpcb.9b04474.
Hu, Xiaohu, Smith, Micholas Dean, Humphreys, Bailey M., Green, Adam T., Parks, Jerry M., Baudry, Jerome Y., & Smith, Jeremy C. Ligand-Dependent Sodium Ion Dynamics within the A2A Adenosine Receptor: A Molecular Dynamics Study. United States. doi:10.1021/acs.jpcb.9b04474.
Hu, Xiaohu, Smith, Micholas Dean, Humphreys, Bailey M., Green, Adam T., Parks, Jerry M., Baudry, Jerome Y., and Smith, Jeremy C. Wed . "Ligand-Dependent Sodium Ion Dynamics within the A2A Adenosine Receptor: A Molecular Dynamics Study". United States. doi:10.1021/acs.jpcb.9b04474.
@article{osti_1561656,
title = {Ligand-Dependent Sodium Ion Dynamics within the A2A Adenosine Receptor: A Molecular Dynamics Study},
author = {Hu, Xiaohu and Smith, Micholas Dean and Humphreys, Bailey M. and Green, Adam T. and Parks, Jerry M. and Baudry, Jerome Y. and Smith, Jeremy C.},
abstractNote = {Sodium ions have long been known to reduce the binding of agonists in many class-A GPCRs while having little effect on antagonist binding. In this study, using long-time scale classical all-atom molecular dynamics simulations, we explore, in atomic detail, the motion of sodium ions within the ligand-binding pocket of the A2A adenosine receptor (A2A-AR) both in the presence and absence of ligands and in the active and inactive state. We identify novel secondary ion binding sites within the pocket and find that the types of ion motions within the pocket are highly dependent on the presence and type of ligand within the pocket. Finally, our results provide a first step toward developing a molecular understanding of the impact of sodium ions on class-A GPCRs.},
doi = {10.1021/acs.jpcb.9b04474},
journal = {Journal of Physical Chemistry. B, Condensed Matter, Materials, Surfaces, Interfaces and Biophysical Chemistry},
number = 38,
volume = 123,
place = {United States},
year = {2019},
month = {9}
}

Journal Article:
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This content will become publicly available on September 4, 2020
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