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Degradation of pesticides diazinon and diazoxon by phosphotriesterase: insight into divergent mechanisms from QM/MM and MD simulations
Physical Chemistry Chemical Physics ( IF 2.9 ) Pub Date : 2021-12-06 , DOI: 10.1039/d1cp05034f Yuzhuang Fu 1 , Yuwei Zhang 1 , Fangfang Fan 2 , Binju Wang 1 , Zexing Cao 1
Physical Chemistry Chemical Physics ( IF 2.9 ) Pub Date : 2021-12-06 , DOI: 10.1039/d1cp05034f Yuzhuang Fu 1 , Yuwei Zhang 1 , Fangfang Fan 2 , Binju Wang 1 , Zexing Cao 1
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Enzymatic hydrolysis by phosphotriesterase (PTE) is one of the most effective ways of degrading organophosphorus pesticides, but the catalytic efficiency depends on the structural features of substrates. Here the enzymatic degradation of diazinon (DIN) and diazoxon (DON), characterized by P![[double bond, length as m-dash]](https://www.rsc.org/images/entities/char_e001.gif)
S and PO, respectively, have been investigated by QM/MM calculations and MM MD simulations. Our calculations demonstrate that the hydrolysis of DON (with PO) is inevitably initiated by the nucleophilic attack of the bridging-OH− on the phosphorus center, while for DIN (with PS), we proposed a new degradation mechanism, initiated by the nucleophilic attack of the Znα-bound water molecule, for its low-energy pathway. For both DIN and DON, the hydrolytic reaction is predicted to be the rate-limiting step, with energy barriers of 18.5 and 17.7 kcal mol−1, respectively. The transportation of substrates to the active site, the release of the leaving group and the degraded product are generally verified to be favorable by MD simulations via umbrella sampling, both thermodynamically and dynamically. The side-chain residues Phe132, Leu271 and Tyr309 play the gate-switching role to manipulate substrate delivery and product release. In comparison with the DON-enzyme system, the degraded product of DIN is more easily released from the active site. These new findings will contribute to the comprehensive understanding of the enzymatic degradation of toxic organophosphorus compounds by PTE.
中文翻译：
磷酸三酯酶降解农药二嗪农和二氮唑酮：从 QM/MM 和 MD 模拟中深入了解不同机制
磷酸三酯酶（PTE）酶解是降解有机磷农药最有效的方法之一，但其催化效率取决于底物的结构特征。在这里，通过 QM/MM 计算和 MM MD 模拟研究了分别以 PS 和 P O 为特征的二嗪农 (DIN) 和重氮磷 (DON) 的酶降解。我们的计算表明，DON（与 P O）的水解不可避免地由桥连-OH -对磷中心的亲核攻击引发，而对于 DIN（与 P S），我们提出了一种新的降解机制，由Zn α 的亲核攻击结合水分子，因为它的低能量途径。对于 DIN 和 DON，水解反应预计是限速步骤，能垒分别为 18.5 和 17.7 kcal mol -1。基板的活性位点的运输，离去基团和降解产物的释放一般被证实是有利的通过分子动力学模拟经由伞式采样，热力学和动态。侧链残基 Phe132、Leu271 和 Tyr309 发挥门控开关作用以控制底物递送和产物释放。与DON-酶系统相比，DIN的降解产物更容易从活性位点释放出来。这些新发现将有助于全面了解 PTE 对有毒有机磷化合物的酶促降解。
更新日期：2021-12-20
S and PO, respectively, have been investigated by QM/MM calculations and MM MD simulations. Our calculations demonstrate that the hydrolysis of DON (with PO) is inevitably initiated by the nucleophilic attack of the bridging-OH− on the phosphorus center, while for DIN (with PS), we proposed a new degradation mechanism, initiated by the nucleophilic attack of the Znα-bound water molecule, for its low-energy pathway. For both DIN and DON, the hydrolytic reaction is predicted to be the rate-limiting step, with energy barriers of 18.5 and 17.7 kcal mol−1, respectively. The transportation of substrates to the active site, the release of the leaving group and the degraded product are generally verified to be favorable by MD simulations via umbrella sampling, both thermodynamically and dynamically. The side-chain residues Phe132, Leu271 and Tyr309 play the gate-switching role to manipulate substrate delivery and product release. In comparison with the DON-enzyme system, the degraded product of DIN is more easily released from the active site. These new findings will contribute to the comprehensive understanding of the enzymatic degradation of toxic organophosphorus compounds by PTE.
中文翻译：
磷酸三酯酶降解农药二嗪农和二氮唑酮：从 QM/MM 和 MD 模拟中深入了解不同机制
磷酸三酯酶（PTE）酶解是降解有机磷农药最有效的方法之一，但其催化效率取决于底物的结构特征。在这里，通过 QM/MM 计算和 MM MD 模拟研究了分别以 P
S 和 P O 为特征的二嗪农 (DIN) 和重氮磷 (DON) 的酶降解。我们的计算表明，DON（与 P O）的水解不可避免地由桥连-OH -对磷中心的亲核攻击引发，而对于 DIN（与 P S），我们提出了一种新的降解机制，由Zn α 的亲核攻击结合水分子，因为它的低能量途径。对于 DIN 和 DON，水解反应预计是限速步骤，能垒分别为 18.5 和 17.7 kcal mol -1。基板的活性位点的运输，离去基团和降解产物的释放一般被证实是有利的通过分子动力学模拟经由伞式采样，热力学和动态。侧链残基 Phe132、Leu271 和 Tyr309 发挥门控开关作用以控制底物递送和产物释放。与DON-酶系统相比，DIN的降解产物更容易从活性位点释放出来。这些新发现将有助于全面了解 PTE 对有毒有机磷化合物的酶促降解。
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