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@ARTICLE{Cao:256135,
author = {Cao, Ruyin and Rossetti, Giulia and Bauer, Andreas and
Carloni, Paolo},
title = {{B}inding of the {A}ntagonist {C}affeine to the {H}uman
{A}denosine {R}eceptor h{A}2{AR} in {N}early {P}hysiological
{C}onditions},
journal = {PLoS one},
volume = {10},
number = {5},
issn = {1932-6203},
publisher = {PLoS},
reportid = {FZJ-2015-06144},
pages = {e0126833},
year = {2015},
abstract = {Lipid composition may significantly affect membrane
proteins function, yet its impact on the protein structural
determinants is not well understood. Here we present a
comparative molecular dynamics (MD) study of the human
adenosine receptor type 2A (hA(2A)R) in complex with
caffeine--a system of high neuro-pharmacological
relevance--within different membrane types. These are POPC,
mixed POPC/POPE and cholesterol-rich membranes. 0.8-μs MD
simulations unambiguously show that the helical folding of
the amphipathic helix 8 depends on membrane contents. Most
importantly, the distinct cholesterol binding into the cleft
between helix 1 and 2 stabilizes a specific caffeine-binding
pose against others visited during the simulation. Hence,
cholesterol presence $(~33\%-50\%$ in synaptic membrane in
central nervous system), often neglected in X-ray
determination of membrane proteins, affects the population
of the ligand binding poses. We conclude that including a
correct description of neuronal membranes may be very
important for computer-aided design of ligands targeting
hA(2A)R and possibly other GPCRs.},
cin = {INM-2 / INM-9 / IAS-5 / JSC / GRS Jülich ; German Research
School for Simulation Sciences},
ddc = {500},
cid = {I:(DE-Juel1)INM-2-20090406 / I:(DE-Juel1)INM-9-20140121 /
I:(DE-Juel1)IAS-5-20120330 / I:(DE-Juel1)JSC-20090406 /
I:(DE-Juel1)GRS-20100316},
pnm = {571 - Connectivity and Activity (POF3-571) / 511 -
Computational Science and Mathematical Methods (POF3-511)},
pid = {G:(DE-HGF)POF3-571 / G:(DE-HGF)POF3-511},
typ = {PUB:(DE-HGF)16},
UT = {WOS:000354921400079},
pubmed = {pmid:25992797},
doi = {10.1371/journal.pone.0126833},
url = {https://juser.fz-juelich.de/record/256135},
}