title: Computational study of the binding modes of caffeine to the adenosine A2A receptor.
abstract: Using the recently solved crystal structure of the human adenosine A(2A) receptor, we applied MM/PBSA to compare the binding modes of caffeine with those of the high-affinity selective antagonist ZM241385. MD simulations were performed in the environment of the lipid membrane bilayer. Four low-energy binding modes of caffeine-A(2A) were found, all of which had similar energies. Assuming an equal contribution of each binding mode of caffeine, the computed binding free energy difference between caffeine and ZM241385 is -2.4 kcal/mol, which compares favorably with the experimental value, -3.6 kcal/mol. The configurational entropy contribution of -0.9 kcal/mol from multiple binding modes of caffeine helps explain how a small molecule like caffeine can compete with a significantly larger molecule, ZM241385, which can form many more interactions with the receptor. We also performed residue-wise energy decomposition and found that Phe168, Leu249, and Ile274 contribute most significantly to the binding modes of caffeine and ZM241385.
authors.affiliation: Department of Chemistry and Chemical Biology, McMaster University, 1280 Main Street West, Hamilton, ON L8S4M1, Canada.
authors.forename: Yuli
authors.initials: Y
authors.lastname: Liu
authors.forename: Steven K
authors.initials: SK
authors.lastname: Burger
authors.forename: Paul W
authors.initials: PW
authors.lastname: Ayers
authors.forename: Esteban
authors.initials: E
authors.lastname: Vöhringer-Martinez
mesh_terms: D019943:Amino Acid Substitution; D002110:Caffeine / Q000737:chemistry / Q000378:metabolism*; D019277:Entropy; D006801:Humans; D008051:Lipid Bilayers / Q000737:chemistry / Q000378:metabolism; D056004:Molecular Dynamics Simulation; D016297:Mutagenesis, Site-Directed; D011485:Protein Binding; D017434:Protein Structure, Tertiary; D043705:Receptor, Adenosine A2A / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D014227:Triazines / Q000737:chemistry / Q000378:metabolism; D014230:Triazoles / Q000737:chemistry / Q000378:metabolism
chemical_list: D008051:Lipid Bilayers; D043705:Receptor, Adenosine A2A; D014227:Triazines; D014230:Triazoles; C097270:ZM 241385; D002110:Caffeine