State Key Laboratory of Physical Chemistry of Solid Surfaces and Fujian Provincial Key Laboratory of Theoretical and Computational Chemistry, College of Chemistry and Chemical Engineering, Xiamen University, Xiamen 361005, China.
J Phys Chem B. 2023 Aug 31;127(34):7462-7471. doi: 10.1021/acs.jpcb.3c03952. Epub 2023 Aug 16.
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-enantiomer. Here, the whole enzymatic degradation of both S and R 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-VR are 19.8 kcal mol by the variant with water as a nucleophile and 22.0 kcal mol 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-VR. The hydrolysis of R-VR is triggered only by the hydroxide with an energy span of 20.6 kcal mol for the wild-type PTE and 20.7 kcal mol 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.
V 型神经毒剂很难被膦酸三酯酶（PTE）降解。有趣的是，BHR-73MNW 的 PTE 变体可以有效地提高 VR 的水解效率，尤其是对其 S 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 和其变体 BHR-73MNW 对 VR 的 S 和 R 对映体的整个酶促降解。目前的结果表明，VR 的降解可以由桥接 OH 和锌结合水分子的亲核攻击引发。QM/MM 预测的 S-VR 水解过程的能量垒由带水的变体以亲核试剂计算为 19.8 kcal mol，以 OH 为亲核试剂的野生型 PTE 计算为 22.0 kcal mol，相应的降解产物分别以单齿和双齿配位模式结合到双核金属位。变体有效地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-VR 的降解效率。R-VR 的水解仅由带羟基的物质触发，野生型 PTE 的能量跨度为 20.6 kcal mol，变体 BHR-73-MNW PTE 的能量跨度为 20.7 kcal mol。对 PTE 对 VR 的立体选择性降解以及水的作用的这种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。
