Ligand-Dependent Sodium Ion Dynamics within the A2A Adenosine Receptor: A Molecular Dynamics Study

Xiaohu Hu; Micholas Dean Smith; Bailey M. Humphreys; Adam T. Green; Jerry M. Parks; Jerome Y. Baudry; Jeremy C. Smith

doi:10.1021/acs.jpcb.9b04474

Ligand-Dependent Sodium Ion Dynamics within the A_2A Adenosine Receptor: A Molecular Dynamics Study

Xiaohu Hu, Micholas Dean Smith, Bailey M. Humphreys, Adam T. Green, Jerry M. Parks, Jerome Y. Baudry, Jeremy C. Smith

Molecular Biophysics

Research output: Contribution to journal › Article › peer-review

4 Scopus citations

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. Here, 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. Our results provide a first step toward developing a molecular understanding of the impact of sodium ions on class-A GPCRs.

Original language	English
Pages (from-to)	7947-7954
Number of pages	8
Journal	Journal of Physical Chemistry B
Volume	123
Issue number	38
DOIs	https://doi.org/10.1021/acs.jpcb.9b04474
State	Published - Sep 26 2019

Funding

This work used resources of the Compute and Data Environment for Science (CADES) at Oak Ridge National Laboratory, which is managed by UT-Battelle, LLC, for the U.S. Department of Energy under Contract DE-AC05-00OR22725. The authors acknowledge funding from the Laboratory Directed Research and Development funds to ORNL from the US DOE.

Funders	Funder number
U.S. Department of Energy	DE-AC05-00OR22725
Oak Ridge National Laboratory
Laboratory Directed Research and Development

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10.1021/acs.jpcb.9b04474

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title = "Ligand-Dependent Sodium Ion Dynamics within the A2A 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. Here, 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. Our results provide a first step toward developing a molecular understanding of the impact of sodium ions on class-A GPCRs.",

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AU - Hu, Xiaohu

AU - Smith, Micholas Dean

AU - Humphreys, Bailey M.

AU - Green, Adam T.

AU - Parks, Jerry M.

AU - Baudry, Jerome Y.

AU - Smith, Jeremy C.

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AB - Sodium ions have long been known to reduce the binding of agonists in many class-A GPCRs while having little effect on antagonist binding. Here, 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. Our results provide a first step toward developing a molecular understanding of the impact of sodium ions on class-A GPCRs.

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Ligand-Dependent Sodium Ion Dynamics within the A_2A Adenosine Receptor: A Molecular Dynamics Study

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