On the mechanism of ATP hydrolysis in F1-ATPase
On the mechanism of ATP hydrolysis in F1-ATPase
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DOI：
10.1016/s0006-3495(03)74650-5
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发表时间：
2003-10-01
影响因子：
3.4
通讯作者：
Schulten, K
中科院分区：
文献类型：
--
作者：
Dittrich, M;Hayashi, S;Schulten, K
生物体内大多数细胞的ATP是由F1Fo - ATP合酶合成的。该酶水溶性的F - 1部分也可逆向工作，利用ATP水解过程中释放的化学能产生机械运动。尽管有大量的生化数据以及F - 1的若干X射线晶体结构，但对于这种蛋白质如何有效地将ATP→H₂O→ADP + Pᵢ反应过程中释放的化学能转化为柄的机械运动，仍然存在相当大的理解缺失。我们在此报道一项对F - 1的β(TP)催化位点中ATP水解的从头算量子力学/分子力学（QM/MM）研究。我们的模拟提供了反应路径、其能量学以及催化过程中核苷酸与蛋白质环境相互作用的原子水平描述。模拟表明，具有最低势能垒的反应路径是通过涉及两个水分子对γ - 磷酸的亲核攻击进行的。此外，发现β(TP)中的ATP水解反应是吸热的，这表明在所研究的特定构象下，催化位点能够支持ATP的合成，而不促进ATP水解。
Most of the cellular ATP in living organisms is synthesized by the enzyme F1Fo-ATP synthase. The water soluble F-1 part of the enzyme can also work in reverse and utilize the chemical energy released during ATP hydrolysis to generate mechanical motion. Despite the availability of a large amount of biochemical data and several x-ray crystallographic structures of F-1, there still remains a considerable lack of understanding as to how this protein efficiently converts the chemical energy released during the reaction ATP --> H2O --> ADP + P-i into mechanical motion of the stalk. We report here an ab initio QM/MM study of ATP hydrolysis in the beta(TP) catalytic site of F-1. Our simulations provide an atomic level description of the reaction path, its energetics, and the interaction of the nucleotide with the protein environment during catalysis. The simulations suggest that the reaction path with the lowest potential energy barrier proceeds via nucleophilic attack on the gamma-phosphate involving two water molecules. Furthermore, the ATP hydrolysis reaction in beta(TP) is found to be endothermic, demonstrating that the catalytic site is able to support the synthesis of ATP and does not promote ATP hydrolysis in the particular conformation studied.