QM/MM and MM MD Simulations on Enzymatic Degradation of the Nerve Agent VR by Phosphotriesterase.

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.