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QM/MM and MM MD simulations on decontamination of the V-type nerve agent VX by phosphotriesterase: toward a comprehensive understanding of steroselectivity and activity
Physical Chemistry Chemical Physics ( IF 2.9 ) Pub Date : 2022-04-18 , DOI: 10.1039/d2cp00773h Fangfang Fan 1, 2 , Yongchao Zheng 3 , Yuzhuang Fu 2 , Yuwei Zhang 2 , He Zheng 3 , Changjiang Lyu 1 , Linyu Chen 1 , Jun Huang 1 , Zexing Cao 2
Physical Chemistry Chemical Physics ( IF 2.9 ) Pub Date : 2022-04-18 , DOI: 10.1039/d2cp00773h Fangfang Fan 1, 2 , Yongchao Zheng 3 , Yuzhuang Fu 2 , Yuwei Zhang 2 , He Zheng 3 , Changjiang Lyu 1 , Linyu Chen 1 , Jun Huang 1 , Zexing Cao 2
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Due to deadly toxicity and high environmental stability of the nerve agent VX, an efficient decontamination approach is desperately needed in tackling its severe threat to human security. The enzymatic destruction of nerve agents has been generally considered as one of the most effective ways, and here the hydrolysis of VX by phosphotriesterase (PTE) was investigated by extensive QM/MM and MM MD simulations. The hydrolytic cleavage of P–S by PTE is a two-step process with the free energy spans of 15.8 and 26.0 kcal mol−1 for the RP- and SP-enantiomer VX, respectively, and such remarkable stereospecificity of VX enantiomers in the enzymatic degradation is attributed to their conformational compatibility with the active pocket. The structurally less adaptive SP-enantiomer allows one additional water molecule to enter the binuclear zinc center and remarkably facilitates the release of the degraded product. Overall, the rate-limiting steps in the enzymatic degradation of VX by PTE involve the degraded product release of the RP-enantiomer and the enzymatic P–S cleavage of the SP-enantiomer. Further computational analysis on the mutation of selected residues also revealed that H257Y, H257D, H254Q-H257F, and L7ep-3a variants allow more water molecules to enter the active site, which improves the catalytic efficiency of PTE, as observed experimentally. The present work provides mechanistic insights into the stereoselective hydrolysis of VX by PTE and the activity manipulation through the active-site accessibility of water molecules, which can be used for the enzyme engineering to defeat chemical warfare agents.
中文翻译：
磷酸三酯酶对 V 型神经毒剂 VX 去污的 QM/MM 和 MM MD 模拟：全面了解立体选择性和活性
由于神经毒剂 VX 具有致命的毒性和高度的环境稳定性，因此迫切需要一种有效的净化方法来应对其对人类安全的严重威胁。神经毒剂的酶促破坏通常被认为是最有效的方法之一，这里通过广泛的 QM/MM 和 MM MD 模拟研究了磷酸三酯酶 (PTE) 对 VX 的水解。PTE 对 P-S 的水解裂解是一个两步过程，R P - 和 S P 的自由能跨度分别为15.8和26.0 kcal mol -1-对映异构体 VX 分别是 VX 对映异构体在酶促降解中的这种显着立体特异性归因于它们与活性口袋的构象相容性。结构上适应性较差的S P对映异构体允许一个额外的水分子进入双核锌中心，并显着促进降解产物的释放。总体而言，PTE 酶促降解 VX 的限速步骤涉及R P对映异构体的降解产物释放和S P的酶促 P-S 裂解-对映异构体。对选定残基突变的进一步计算分析还表明，H257Y、H257D、H254Q-H257F 和 L7ep-3a 变体允许更多的水分子进入活性位点，从而提高了 PTE 的催化效率，如实验所见。目前的工作为 PTE 对 VX 的立体选择性水解和通过水分子的活性位点可及性进行的活性操纵提供了机理见解，可用于酶工程以击败化学战剂。
更新日期：2022-04-18
中文翻译：
磷酸三酯酶对 V 型神经毒剂 VX 去污的 QM/MM 和 MM MD 模拟：全面了解立体选择性和活性
由于神经毒剂 VX 具有致命的毒性和高度的环境稳定性，因此迫切需要一种有效的净化方法来应对其对人类安全的严重威胁。神经毒剂的酶促破坏通常被认为是最有效的方法之一，这里通过广泛的 QM/MM 和 MM MD 模拟研究了磷酸三酯酶 (PTE) 对 VX 的水解。PTE 对 P-S 的水解裂解是一个两步过程，R P - 和 S P 的自由能跨度分别为15.8和26.0 kcal mol -1-对映异构体 VX 分别是 VX 对映异构体在酶促降解中的这种显着立体特异性归因于它们与活性口袋的构象相容性。结构上适应性较差的S P对映异构体允许一个额外的水分子进入双核锌中心，并显着促进降解产物的释放。总体而言，PTE 酶促降解 VX 的限速步骤涉及R P对映异构体的降解产物释放和S P的酶促 P-S 裂解-对映异构体。对选定残基突变的进一步计算分析还表明，H257Y、H257D、H254Q-H257F 和 L7ep-3a 变体允许更多的水分子进入活性位点，从而提高了 PTE 的催化效率，如实验所见。目前的工作为 PTE 对 VX 的立体选择性水解和通过水分子的活性位点可及性进行的活性操纵提供了机理见解，可用于酶工程以击败化学战剂。
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