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 (hA2AR) 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 hA2AR and possibly other GPCRs.
Highlights
Emerging experiments point to an important role of membrane lipid composition in structure/function relationships of G-protein coupled receptors (GPCRs)—the largest membrane protein family in mammals [1,2,3,4]
In rhodopsin, adding (1-palmitoyl2-oleoylphosphatidylethanolamine) POPE lipids into POPC (1-palmitoyl-2-oleoylphosphatidylcholine) lipid bilayers affect the equilibrium between two sub-states of the rhodopsin functional cycle [5,6]
The artificial environment is found here to affect the population of ligand poses drastically: the pose found in the X-ray structure, at 3.6-Å of resolution, is the most populated one in none of our 0.8 μs-long molecular dynamics (MD) simulations
Summary
Emerging experiments point to an important role of membrane lipid composition in structure/function relationships of G-protein coupled receptors (GPCRs)—the largest membrane protein family in mammals [1,2,3,4]. In rhodopsin, adding (1-palmitoyl2-oleoylphosphatidylethanolamine) POPE lipids into POPC (1-palmitoyl-2-oleoylphosphatidylcholine) lipid bilayers affect the equilibrium between two sub-states of the rhodopsin functional cycle [5,6]. Another example is given by the class A GPCR serotonin1A receptor: its binding to the agonist 8-OH-DPAT decreases with cholesterol concentration [7]. This issue is crucial for pharmacological applications, as more than one quarter of FDA-approved drugs target GPCRs [8].
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