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Title: Pathways and Mechanism of Caffeine Binding to Human Adenosine A2A Receptor

Abstract

Caffeine (CFF) is a common antagonist to the four subtypes of adenosine G-protein-coupled receptors (GPCRs), which are critical drug targets for treating heart failure, cancer, and neurological diseases. However, the pathways and mechanism of CFF binding to the target receptors remain unclear. In this study, we have performed all-atom-enhanced sampling simulations using a robust Gaussian-accelerated molecular dynamics (GaMD) method to elucidate the binding mechanism of CFF to human adenosine A2A receptor (A2AAR). Multiple 500–1,000 ns GaMD simulations captured both binding and dissociation of CFF in the A2AAR. The GaMD-predicted binding poses of CFF were highly consistent with the x-ray crystal conformations with a characteristic hydrogen bond formed between CFF and residue N6.55 in the receptor. In addition, a low-energy intermediate binding conformation was revealed for CFF at the receptor extracellular mouth between ECL2 and TM1. While the ligand-binding pathways of the A2AAR were found similar to those of other class A GPCRs identified from previous studies, the ECL2 with high sequence divergence serves as an attractive target site for designing allosteric modulators as selective drugs of the A2AAR.

Authors:
 [1];  [1];  [1]
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  1. Univ. of Kansas, Lawrence, KS (United States)
Publication Date:
Research Org.:
Univ. of California, Oakland, CA (United States)
Sponsoring Org.:
USDOE Office of Science (SC), Basic Energy Sciences (BES). Scientific User Facilities Division
OSTI Identifier:
1816986
Grant/Contract Number:  
AC02-05CH11231
Resource Type:
Accepted Manuscript
Journal Name:
Frontiers in Molecular Biosciences
Additional Journal Information:
Journal Volume: 8; Journal ID: ISSN 2296-889X
Publisher:
Frontiers Media S.A.
Country of Publication:
United States
Language:
English
Subject:
59 BASIC BIOLOGICAL SCIENCES; adenosine A2A receptor; caffeine; Gaussian accelerated molecular dynamics; ligand binding; mechanism; pathways

Citation Formats

Do, Hung N., Akhter, Sana, and Miao, Yinglong. Pathways and Mechanism of Caffeine Binding to Human Adenosine A2A Receptor. United States: N. p., 2021. Web. doi:10.3389/fmolb.2021.673170.
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Do, Hung N., Akhter, Sana, & Miao, Yinglong. Pathways and Mechanism of Caffeine Binding to Human Adenosine A2A Receptor. United States. https://doi.org/10.3389/fmolb.2021.673170
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Do, Hung N., Akhter, Sana, and Miao, Yinglong. Tue . "Pathways and Mechanism of Caffeine Binding to Human Adenosine A2A Receptor". United States. https://doi.org/10.3389/fmolb.2021.673170. https://www.osti.gov/servlets/purl/1816986.
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@article{osti_1816986,
title = {Pathways and Mechanism of Caffeine Binding to Human Adenosine A2A Receptor},
author = {Do, Hung N. and Akhter, Sana and Miao, Yinglong},
abstractNote = {Caffeine (CFF) is a common antagonist to the four subtypes of adenosine G-protein-coupled receptors (GPCRs), which are critical drug targets for treating heart failure, cancer, and neurological diseases. However, the pathways and mechanism of CFF binding to the target receptors remain unclear. In this study, we have performed all-atom-enhanced sampling simulations using a robust Gaussian-accelerated molecular dynamics (GaMD) method to elucidate the binding mechanism of CFF to human adenosine A2A receptor (A2AAR). Multiple 500–1,000 ns GaMD simulations captured both binding and dissociation of CFF in the A2AAR. The GaMD-predicted binding poses of CFF were highly consistent with the x-ray crystal conformations with a characteristic hydrogen bond formed between CFF and residue N6.55 in the receptor. In addition, a low-energy intermediate binding conformation was revealed for CFF at the receptor extracellular mouth between ECL2 and TM1. While the ligand-binding pathways of the A2AAR were found similar to those of other class A GPCRs identified from previous studies, the ECL2 with high sequence divergence serves as an attractive target site for designing allosteric modulators as selective drugs of the A2AAR.},
doi = {10.3389/fmolb.2021.673170},
journal = {Frontiers in Molecular Biosciences},
number = ,
volume = 8,
place = {United States},
year = {Tue Apr 27 00:00:00 EDT 2021},
month = {Tue Apr 27 00:00:00 EDT 2021}
}
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https://doi.org/10.3389/fmolb.2021.673170
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