Title: A Comprehensive Understanding of Enzymatic Degradation of the G-type Nerve Agent by Phosphotriesterase: Revised Role of Water Molecules and Rate-Limiting Product Release

Authors: Fangfang Fan,Yongchao Zheng,Yuwei Zhang,He ZHENG,Jin-Yi Zhong,Zexing Cao

Abstract:

The nerve agents are belong to highly toxic organophosphorus compounds, and the wild-type phosphotriesterase (PTE) enzyme is capable of hydrolyzing these organophosphates but with a low catalytic efficiency. Here the whole enzymatic detoxification process of the G-type nerve agent sarin by the PTE enzyme, including the substrate delivery, the chemical reaction, and the product release, has been explored by extensive QM/MM MD and MM MD simulations. The plausible mechanisms for the chemical and nonchemical steps, the roles of water molecules and key residues have been discussed. The enzymatic P-F cleavage of sarin is a two-step exothermic process with the free energy span of 12.3 kcal/mol, and it should be facile in the whole enzymatic catalysis. On the contrary, the initial degraded product is tightly bound to the binuclear zinc center, and its dissociation experiences multiple chemical steps with the free energy barriers of 21.0 kcal/mol for the recombination process and 18.3 kcal/mol for the release of the product phosphoester from the active site. The solvation of hydrophilic products in the bulk water is generally exothermic notably, which provides the driving force for the release of products from the active site. The side-chain residues Leu271 and Phe132 in the transportation channel function as the entrance gate in PTE and play an important gate-switching role to manipulate the substrate access to the active site and the product release. These mechanistic details for the enzymatic degradation of sarin by PTE provide significant clues to improve its activity towards the never agents.

Full-Link: https://pubs.acs.org/doi/10.1021/acscatal.9b01877