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

Nerve agents are 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 the 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 produc...