Pathways and Mechanism of Caffeine Binding to Human Adenosine A2A Receptor

Do, Hung N.; Akhter, Sana; Miao, Yinglong

doi:10.3389/fmolb.2021.673170

Pathways and Mechanism of Caffeine Binding to Human Adenosine A_2A Receptor

Journal Article · Tue Apr 27 00:00:00 EDT 2021 · Frontiers in Molecular Biosciences

DOI:https://doi.org/10.3389/fmolb.2021.673170· OSTI ID:1816986

Do, Hung N. ^[1]; Akhter, Sana ^[2]; Miao, Yinglong ^[2]

Univ. of Kansas, Lawrence, KS (United States); Edgewater Federal Solutions/OSTI
Univ. of Kansas, Lawrence, KS (United States)

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 A_2A receptor (A_2AAR). Multiple 500–1,000 ns GaMD simulations captured both binding and dissociation of CFF in the A_2AAR. 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 A_2AAR 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 A_2AAR.

View Accepted Manuscript (DOE)

Research Organization:: Univ. of California, Oakland, CA (United States)

Sponsoring Organization:: USDOE Office of Science (SC), Basic Energy Sciences (BES). Scientific User Facilities Division

Grant/Contract Number:: AC02-05CH11231

OSTI ID:: 1816986

Journal Information:: Frontiers in Molecular Biosciences, Journal Name: Frontiers in Molecular Biosciences Vol. 8; ISSN 2296-889X

Publisher:: Frontiers Media S.A.Copyright Statement

Country of Publication:: United States

Language:: English

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59 BASIC BIOLOGICAL SCIENCES
Gaussian accelerated molecular dynamics
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caffeine
ligand binding
mechanism
pathways

Pathways and Mechanism of Caffeine Binding to Human Adenosine A2A Receptor

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References (72)

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Pathways and Mechanism of Caffeine Binding to Human Adenosine A_2A Receptor