Reaction pathway and free energy profile for prechemical reaction step of human butyrylcholinesterase-catalyzed hydrolysis of (-)-cocaine by combined targeted molecular dynamics and potential of mean force simulations.
Reaction pathway and free energy profile for prechemical reaction step of human butyrylcholinesterase-catalyzed hydrolysis of (-)-cocaine by combined targeted molecular dynamics and potential of mean force simulations.
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DOI：
10.1021/jp106539w
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发表时间：
2010-10-28
影响因子：
3.3
通讯作者：
Zhan, Chang-Guo
中科院分区：
文献类型：
--
作者：
Huang, Xiaoqin;Pan, Yongmei;Zheng, Fang;Zhan, Chang-Guo
结合靶向分子动力学 (TMD) 和平均力势 (PMF) 模拟，揭示了详细的途径，并确定了从非预反应性丁酰胆碱酯酶 (BChE)-(−)-可卡因结合到与 BChE 结合袋中 (−)-可卡因旋转相关的预反应性 BChE-(−)-可卡因结合的结构转变的相应自由能曲线。研究表明，结构转变涉及两个过渡态（TS1rot 和 TS2rot）。 TS1rot 主要与非前反应复合物的变形相关，而 TS2rot 主要与前反应复合物的形成相关。还证明，A328W/Y332G 突变显着降低了 BChE 结合口袋中 (-)-可卡因旋转的空间位阻，从而降低了从非预反应性结合到预反应性结合的结构转变的自由能障碍。计算出的相对自由能垒均与现有的实验动力学数据一致。本研究中获得的新机制见解和测试的新计算协议对于 BChE 高活性突变体的未来计算设计应该有价值。基于 TMD 和 PMF 组合模拟的通用计算策略和方法对于涉及配体旋转或蛋白质结合袋中另一种类型的结构转变的其他类似机械问题的详细途径和自由能分布的计算研究也可能很有价值。
Combined targeted molecular dynamics (TMD) and potential of mean force (PMF) simulations have been carried out to uncover the detailed pathway and determine the corresponding free energy profile for the structural transformation from the nonprereactive butyrylcholinesterase (BChE)-(−)-cocaine binding to the prereactive BChE-(−)-cocaine binding associated with the (−)-cocaine rotation in the binding pocket of BChE. It has been shown that the structural transformation involves two transition states (TS1rot and TS2rot). TS1rot is mainly associated with the deformation of the nonprereactive complex, whereas TS2rot is mainly associated with the formation of the prereactive complex. It has also been demonstrated that the A328W/Y332G mutation significantly reduces the steric hindrance for (−)-cocaine rotation in the binding pocket of BChE and, thus, decreases the free energy barrier for the structural transformation from the nonprereactive binding to the prereactive binding. The calculated relative free energy barriers are all consistent with available experimental kinetic data. The new mechanistic insights obtained and the novel computational protocol tested in this study should be valuable for future computational design of high-activity mutants of BChE. The general computational strategy and approach based on the combined TMD and PMF simulations may be also valuable in computational studies of detailed pathways and free energy profiles for other similar mechanistic problems involving ligand rotation or another type of structural transformation in the binding pocket of a protein.
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影响因子：
3.3
作者：
Gao, DQ;Zhan, CG
通讯作者：
Zhan, CG
影响因子：
4.4
作者：
Eyring, H
通讯作者：
Eyring, H
DOI：
10.1073/pnas.0507332102
发表时间：
2005-11-15
影响因子：
11.1
作者：
Pan, YM;Gao, DQ;Zhan, CG
通讯作者：
Zhan, CG
影响因子：
4.4
作者：
JORGENSEN, WL;CHANDRASEKHAR, J;KLEIN, ML
通讯作者：
KLEIN, ML
影响因子：
3.3
作者：
Hamza, A;Cho, H;Zhan, CG
通讯作者：
Zhan, CG