Organophosphorus (OP) compounds are among the most toxic chemical substances and are widely used as insecticides, pesticides and chemical warfare agents. Organophosphorus hydrolase (OPH), also called phophotriesterase, is a metalloenzyme that can hydrolyze OP agents and the hydrolysis products are generally of reduced toxicity relative to their parent compounds. The best OPH substrate found to date is diethyl p-nitrophenyl phosphate (paraoxon). Most structural and kinetic studies assume that the binding orientation of paraoxon is identical to that of diethyl 4-methylbenzylphosphonate, which is the only substrate analog co-crystallized with OPH. In the current work, we present a docking study followed by molecular dynamics (MD) simulations to identify the correct binding mode of paraoxon. Then, we compare the binding modes of paraoxon and diethyl 4-methylbenzylphosphonate. The observed interactions between each compound and the protein provide valuable information regarding the chemical mechanism of hydrolysis. Additionally, crystallographic structures show that significant rearrangements have occurred in several specific regions between the apo- and holoenzyme forms. Therefore, we have performed MD simulations on the apoenzyme structure to explain the interactions in the active site upon ligand binding.<br/><br/>

Identification of the binding mode of diethyl p-nitrophenyl phosphate to phosphotriesterase

2019 Fall National Meeting

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