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

Abstract

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 Sp-enantiomer. Here, the whole enzymatic degradation of both Sp and Rp 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 Sp-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 Sp-VR. The hydrolysis of Rp-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.

Elucidating the degradation mechanism of the nerve agent A-234 using various detergents: a theoretical investigation

“…Great efforts have been made to decontaminate NAs effectively, both experimentally and theoretically. 7–27 Metal–organic frameworks (MOFs), leveraging their catalytic properties, have demonstrated that they can facilitate the degradation of NAs. 7–13 Additionally, various metal oxides, such as MgO, Al 2 O 3 , TiO 2 , Cu 2 O, CuO, and ZnO, have considerable potential for adsorbing and decomposing NAs.…”

“…14–21 The biodegradation of NAs by enzymes under mild conditions, such as phosphotriesterase (PTE) successfully used in degrading organophosphorus pesticides, has also received considerable interest. 22–27…”

Elucidating the Enzymatic Mechanism of Dihydrocoumarin Degradation: Insight into the Functional Evolution of Methyl-Parathion Hydrolase from QM/MM and MM MD Simulations

“…Organophosphorus pesticides, such as paraoxon, diazoxon, and methyl-parathion, are widely used in agriculture and pose significant toxicity risks. − Enzymatic degradation by MPH enzymes represents one of the most effective methods for hydrolyzing MPIN. − The phosphotriesterase (PTE) enzyme is also renowned for its ability to degrade phosphorus pesticides. − As depicted in Figure S2, the active-site structure of the PTE enzyme bears a similarity to that of MPH. In the active site of PTE, there are three distinct pockets that correspond to three groups of phosphorus pesticides (see Figure S2c).…”