title: Binding of the Antagonist Caffeine to the Human Adenosine Receptor hA2AR in Nearly Physiological Conditions.
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.
authors.affiliation: German Research School for Simulation Sciences (joint venture of RWTH Aachen University and Forschungszentrum Jülich GmbH), D-52425, Jülich, Germany; Computational Biomedicine, Institute for Advanced Simulation (IAS-5), Forschungszentrum Jülich GmbH, D-52425, Jülich, Germany.
authors.forename: Ruyin
authors.initials: R
authors.lastname: Cao
authors.affiliation: German Research School for Simulation Sciences (joint venture of RWTH Aachen University and Forschungszentrum Jülich GmbH), D-52425, Jülich, Germany; Computational Biomedicine, Institute for Advanced Simulation (IAS-5), Forschungszentrum Jülich GmbH, D-52425, Jülich, Germany; Institute of Neuroscience and Medicine (INM-9), Forschungszentrum Jülich GmbH, D-52425, Jülich, Germany; Jülich Supercomputing Centre (JSC), Forschungszentrum Jülich GmbH, D-52425, Jülich, Germany.
authors.forename: Giulia
authors.initials: G
authors.lastname: Rossetti
authors.affiliation: Institute of Neuroscience and Medicine (INM-2), Forschungszentrum Jülich GmbH, D-52425, Jülich, Germany.
authors.forename: Andreas
authors.initials: A
authors.lastname: Bauer
authors.affiliation: German Research School for Simulation Sciences (joint venture of RWTH Aachen University and Forschungszentrum Jülich GmbH), D-52425, Jülich, Germany; Computational Biomedicine, Institute for Advanced Simulation (IAS-5), Forschungszentrum Jülich GmbH, D-52425, Jülich, Germany; Institute of Neuroscience and Medicine (INM-9), Forschungszentrum Jülich GmbH, D-52425, Jülich, Germany.
authors.forename: Paolo
authors.initials: P
authors.lastname: CarIoni
mesh_terms: D058917:Adenosine A2 Receptor Antagonists / Q000737:chemistry / Q000378:metabolism*; D002110:Caffeine / Q000737:chemistry / Q000378:metabolism*; D002784:Cholesterol / Q000378:metabolism; D006801:Humans; D008024:Ligands; D008567:Membranes, Artificial; D008958:Models, Molecular; D011485:Protein Binding / Q000187:drug effects; D017433:Protein Structure, Secondary; D043705:Receptor, Adenosine A2A / Q000737:chemistry / Q000378:metabolism*
chemical_list: D058917:Adenosine A2 Receptor Antagonists; D008024:Ligands; D008567:Membranes, Artificial; D043705:Receptor, Adenosine A2A; D002110:Caffeine; D002784:Cholesterol