Acetylcholinesterase is a key enzyme that terminates synaptic signals. Organophosphates can covalently inhibit AChE by phosphonylating the enyzme's catalytic residue. These phosphonylated adducts can either be reactivated by nucleophilic compounds or undergo an aging reaction, leading to irreversible AChE inhibition and overstimulation of the nervous system. By employing ab initio QM/MM molecular dynamics simulations with umbrella sampling, we characterized the covalent inhibition mechanism of AChE by nerve agent soman, in which the phosphonylation reaction follows an associative nucleophilic substitution mechanism, and the aging reaction follows a modified methyl-migration scheme, which is initiated with excision of soman's alkyl group. Our simulations provide detailed mechanistic insights into the aging process, which is a key to development of novel strategies to reduce the toxic effects of organophosphate poisoning. Therefore, the present work is expected facilitate design of novel reactivating compounds and aging-resistant pseudo-catalytic scavengers capable of sequestering organophosphates.

Irreversible inhibition mechanism of acetylcholinesterase and soman determined by Born-Oppenheimer <i>ab initio</i> QM/MM molecular dynamics simulations

245th National Meeting (2013)

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Irreversible inhibition mechanism of acetylcholinesterase and soman determined by Born-Oppenheimer ab initio QM/MM molecular dynamics simulations