Mechanism of the myosin catalyzed hydrolysis of ATP as rationalized by molecular modeling
Mechanism of the myosin catalyzed hydrolysis of ATP as rationalized by molecular modeling
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DOI：
10.1073/pnas.0701727104
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发表时间：
2007-04-24
影响因子：
11.1
通讯作者：
Nemukhin, Alexander V.
中科院分区：
文献类型：
--
作者：
Grigorenko, Bella L.;Rogov, Alexander V.;Nemukhin, Alexander V.
肌球蛋白催化的三磷酸腺苷 (ATP) 水解的内在化学反应通过使用量子力学和分子力学 (QM/MM) 相结合的方法进行建模，该方法实现了整个模型的近乎从头开始的表示。从肌球蛋白与 ATP 类似物 ADP-VO4- 结合的晶体结构（蛋白质数据库 ID 代码 1VOM）的重原子衍生的坐标开始，找到了 ATP + H2O -> ADP + P-i 转化的最小能量路径，其特征在于两个不同的事件：(t) P-gamma-O-beta γ 键的低活化能裂解以及 γ-磷酸盐与 ADP 的分离，以及 (h) 形成无机磷酸盐是由两个水分子介导并由蛋白质的 Glu-459-Arg-238 盐桥协助的质子转移的结果。酶-底物复合物的最小能量模型具有稳定的氢键网络，其中溶解水的位置有利于 ATP γ-磷酸的亲核攻击以及质子转移到稳定结合的第二水。此外，P-γ-O-β γ 键已变得明显比 ATP 未结合状态下的更长，因此易于裂解。建模的转化被视为在 ATP 与肌球蛋白紧密结合之后、在无机磷酸盐释放之前的构象变化之前发生在封闭酶袋中的整个水解反应的一部分。
The intrinsic chemical reaction of adenosine triphosphate (ATP) hydrolysis catalyzed by myosin is modeled by using a combined quantum mechanics and molecular mechanics (QM/MM) methodology that achieves a near ab initio representation of the entire model. Starting with coordinates derived from the heavy atoms of the crystal structure (Protein Data Bank ID code 1VOM) in which myosin is bound to the ATP analog ADP-VO4-, a minimum-energy path is found for the transformation ATP + H2O -> ADP + P-i that is characterized by two distinct events: (t) a low activation-energy cleavage of the P-gamma-O-beta gamma bond and separation of the gamma-phosphate from ADP and (h) the formation of the inorganic phosphate as a consequence of proton transfers mediated by two water molecules and assisted by the Glu-459-Arg-238 salt bridge of the protein. The minimum-energy model of the enzyme-substrate complex features a stable hydrogen-bonding network in which the lytic water is positioned favorably for a nucleophilic attack of the ATP gamma-phosphate and for the transfer of a proton to stably bound second water. In addition, the P-gamma-O-beta gamma bond has become significantly longer than in the unbound state of the ATP and thus is predisposed to cleavage. The modeled transformation is viewed as the part of the overall hydrolysis reaction occurring in the closed enzyme pocket after ATP is bound tightly to myosin and before conformational changes preceding release of inorganic phosphate.