QM/MM and MM MD Simulations on Enzymatic Degradation of the Nerve Agent VR by Phosphotriesterase,The Journal of Physical Chemistry B

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QM/MM and MM MD Simulations on Enzymatic Degradation of the Nerve Agent VR by Phosphotriesterase
The Journal of Physical Chemistry B ( IF 2.8 ) Pub Date : 2023-08-16 , DOI: 10.1021/acs.jpcb.3c03952
Jun Yu ₁ , Yuzhuang Fu ₁ , Zexing Cao ₁

Affiliation

V-type nerve agents are hardly degraded by phosphotriesterase (PTE). Interestingly, the PTE variant of BHR-73MNW can effectively improve the hydrolytic efficiency of VR, especially for its S_p-enantiomer. Here, the whole enzymatic degradation of both S_p and R_p enantiomers of VR by the wild-type PTE and its variant BHR-73MNW was investigated by quantum mechanics/molecular mechanics (QM/MM) calculations and MM molecular dynamics simulations. Present results indicate that the degradation of VR can be initiated by the nucleophilic attack of the bridging OH^– and the zinc-bound water molecule. The QM/MM-predicted energy barriers for the hydrolytic process of S_p-VR are 19.8 kcal mol^–1 by the variant with water as a nucleophile and 22.0 kcal mol^–1 by the wild-type PTE with OH^– as a nucleophile, and corresponding degraded products are bound to the dinuclear metal site in monodentate and bidentate coordination modes, respectively. The variant effectively increases the volume of the large pocket, allowing more water molecules to enter the active pocket and resulting in the improvement of the degradation efficiency of S_p-VR. The hydrolysis of R_p-VR is triggered only by the hydroxide with an energy span of 20.6 kcal mol^–1 for the wild-type PTE and 20.7 kcal mol^–1 for the variant BHR-73-MNW PTE. Such mechanistic insights into the stereoselective degradation of VR by PTE and the role of water may inspire further studies to improve the catalytic efficiency of PTE toward the detoxification of nerve agents.

中文翻译：

磷酸三酯酶酶促降解神经毒剂 VR 的 QM/MM 和 MM MD 模拟

V型神经毒剂很难被磷酸三酯酶（PTE）降解。有趣的是，BHR-73MNW的PTE变体可以有效提高VR的水解效率，尤其是其S _p对映体。在这里，通过量子力学/分子力学（QM/MM）计算和MM分子动力学模拟研究了野生型PTE及其变体BHR-73MNW对VR的S p 和_R p_对映体的整个酶促降解。^{目前的结果表明，VR 的降解可以通过桥接 OH和}锌结合水分子的亲核攻击来引发。对于以水作为亲核试剂的变体， S _p -VR 水解过程的 QM/MM 预测能垒为 19.8 kcal mol ^{–1 ，以 OH}^–作为亲核试剂的野生型 PTE 为22.0 kcal mol ^–1 ，相应的降解产物分别以单齿和双齿配位模式与双核金属位点结合。该变体有效增加了大口袋的体积，允许更多的水分子进入活性口袋，从而提高了S _p -VR的降解效率。_{R p} -VR的水解仅由氢氧化物触发，野生型 PTE 的能量跨度为 20.6 kcal mol ^–1 ，变体 BHR-73-MNW PTE 的能量跨度为20.7 kcal mol ^{–1 。}这种对 PTE 立体选择性降解 VR 和水的作用的机制见解可能会激发进一步的研究，以提高 PTE 对神经毒剂解毒的催化效率。

更新日期：2023-08-16

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