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Hydrolysis of phosphotriesters: A theoretical analysis of the enzymatic and solution mechanisms

机译：磷酸三酯的水解：酶和溶液机理的理论分析

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A theoretical study on the alkaline hydrolysis of paraoxon, one of the most popular organophosphorus pesticides, in aqueous solution and in the active site of Pseudomonas diminuta phosphotriesterase (PTE) is presented. Simulations by means of hybrid quantum mechanics/molecular mechanics (QM/MM) potentials show that the hydrolysis of paraoxon takes place through an A _ND _N or associative mechanism both in solution and in the active site of PTE. The results correctly reproduce the magnitude of the activation free energies and can be used to rationalize the observed kinetic isotope effects (KIEs) for the hydrolysis of paraoxon in both media. Enzymatic hydrolysis of O,O-diethyl p-chlorophenyl phosphate, a phosphotriester having a leaving group with higher pK _a than paraoxon, was also simulated. Hydrolysis of this phosphotriester by PTE follows a A _N+D _N mechanism with a pentacoordinate intermediate. Moreover, the leaving group of this new substrate coordinates to one of the zinc ions of the bimetallic active site in order to stabilize the large negative charge developed on the oxygen atom of the leaving group when the P-O bond is broken in the products state. To accommodate this new ligand in the coordination shell, carbamylated Lys169 must be displaced from one zinc ion to the other, which in turn affects the acidity of Asp301, a residue originally bound to the second zinc ion. This ability to displace some of the ligands of the coordination shell of the zinc centers would explain the promiscuity of this enzyme, which is capable of catalyzing hydrolysis of different substrate by means of different mechanisms. Hydrolysis of paraoxon, one of the most popular organophosphorus pesticides, in the active site of Pseudomonas diminuta phosphotriesterase (PTE) is shown by means of QM/MM simulations to takes place through an A _ND _N or associative mechanism both in solution and in the active site of PTE (see picture).
机译：提出了在水溶液和假单胞菌二磷酸三酯磷酸三酯酶（PTE）的活性部位中对氧磷（一种最流行的有机磷农药）的碱性水解的理论研究。利用混合量子力学/分子力学（QM / MM）电势进行的模拟表明，对氧磷的水解通过溶液中和在PTE的活性位点中通过A _ND _N或缔合机理发生。结果正确地再现了活化自由能的大小，并且可以用来合理化所观察到的动力学对位效应（KIE），以在两种介质中水解对氧磷。还模拟了O，O-二乙基对氯苯基磷酸酯的酶促水解，这是一种磷酸三酯，其离去基团的pK_a比对氧磷高。 PTE对这种磷酸三酯的水解遵循具有五配位中间体的A_N + D_N机理。而且，该新底物的离去基团与双金属活性位点的锌离子之一配位，以便稳定在产物状态下P-O键断裂时在离去基团的氧原子上产生的大量负电荷。为了在配位壳中容纳这种新的配体，必须将氨基甲酰化的Lys169从一个锌离子转移到另一个锌离子，这反过来会影响Asp301的酸性，Asp301是最初与第二个锌离子结合的残基。置换锌中心配位壳的一些配体的能力将解释该酶的混杂性，该酶能够通过不同的机制催化不同底物的水解。通过QM / MM模拟表明，对氧磷是最流行的有机磷农药之一，在Pseudomonas diminuta磷酸三酯酶（PTE）的活性位点中的水解是通过A _ND _N或缔合机制在溶液和活性物质中发生的。 PTE网站（见图）。

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