Department of Chemistry and Chemical Biology, McMaster University, 1280 Main Street West, Hamilton, ON L8S4M1, Canada.
J Phys Chem B. 2011 Dec 1;115(47):13880-90. doi: 10.1021/jp2022049. Epub 2011 Nov 9.
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.
利用最近解析的人源腺苷 A(2A)受体晶体结构，我们应用 MM/PBSA 比较咖啡因与高亲和力选择性拮抗剂 ZM241385 的结合模式。在脂质双层膜环境中进行 MD 模拟。发现咖啡因与 A(2A)受体有 4 种低能量结合模式，能量相似。假设咖啡因的每种结合模式贡献相同，计算得出咖啡因与 ZM241385 的结合自由能差异为-2.4 kcal/mol，与实验值-3.6 kcal/mol 相当。咖啡因的多种结合模式导致构象熵贡献为-0.9 kcal/mol，有助于解释小分子咖啡因如何与 ZM241385 竞争，ZM241385 可以与受体形成更多相互作用。我们还进行了残基能量分解，发现 Phe168、Leu249 和 Ile274 对咖啡因和 ZM241385 的结合模式贡献最大。
