Reaction pathway and free-energy barrier for reactivation of dimethylphosphoryl-inhibited human acetylcholinesterase.
Reaction pathway and free-energy barrier for reactivation of dimethylphosphoryl-inhibited human acetylcholinesterase.
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DOI：
10.1021/jp9055335
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发表时间：
2009-12-17
期刊：
影响因子：
--
通讯作者：
Zhan CG
中科院分区：
文献类型：
--
作者：
Liu J;Zhang Y;Zhan CG
采用第一性原理量子力学/分子力学自由能（QM/MM-FE）方法研究了二甲基磷酰基抑制的人乙酰胆碱酯酶（AChE）偶联物的去磷酸化/再活化机制及相应的自由能分布.基于QM/MM-FE结果，对于有利的反应途径，整个去磷酸化/再活化过程包括三个反应步骤，包括亲核水攻击P原子、二甲基磷酰基的空间重组以及二甲基磷酰基与AChE的Ser 203之间的解离.整个去磷酸化/再活化反应的总自由能垒被认为是从初始反应物到与空间重组步骤相关的过渡态的自由能变化，并且计算的总自由能垒（20.1至23.5千卡/摩尔）合理地接近实验导出的活化自由能22.3千卡/摩尔。此外，关键氨基酸残基及其在反应过程中的具体作用已被确定。
The dephosphorylation/reactivation mechanism and the corresponding free energy profile of dimethylphosphoryl-inhibited conjugate of human acetylcholinesterase (AChE) has been studied by performing first-principles quantum mechanical/molecular mechanical free energy (QM/MM-FE) calculations. Based on the QM/MM-FE results, for the favorable reaction pathway, the entire dephosphorylation/reactivation process consists of three reaction steps, including the nucleophilic water attack on the P atom, the spatial reorganization of the dimethylphosphoryl group, and the dissociation between the dimethylphosphoryl group and Ser203 of AChE. The overall free energy barrier for the entire dephosphorylation/reactivation reaction is found to be the free energy change from the initial reactant to the transition state associated with the spatial reorganization step, and the calculated overall free energy barrier (20.1 to 23.5 kcal/mol) is reasonably close to the experimentally-derived activation free energy of 22.3 kcal/mol. In addition, key amino acid residues and their specific roles in the reaction process have been identified.
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影响因子：
3.3
作者：
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通讯作者：
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影响因子：
4.9
作者：
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影响因子：
56.9
作者：
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DOI：
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发表时间：
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影响因子：
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作者：
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影响因子：
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通讯作者：
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