%0 Journal Article
%A Cao, Ruyin
%A Rossetti, Giulia
%A Bauer, Andreas
%A Carloni, Paolo
%T Binding of the Antagonist Caffeine to the Human Adenosine Receptor hA2AR in Nearly Physiological Conditions
%J PLoS one
%V 10
%N 5
%@ 1932-6203
%I PLoS
%M FZJ-2015-06144
%P e0126833
%D 2015
%X 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.
%F PUB:(DE-HGF)16
%9 Journal Article
%U <Go to ISI:>//WOS:000354921400079
%$ pmid:25992797
%R 10.1371/journal.pone.0126833
%U https://juser.fz-juelich.de/record/256135