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- W2017108174 abstract "Acetylcholinesterase (AChE) is a crucial enzyme in the cholinergic nervous system that hydrolyzes neurotransmitter acetylcholine (ACh) and terminates synaptic signals. The catalytic serine of AChE can be phosphonylated by soman, one of the most potent nerve agents, and subsequently undergo an aging reaction. This phosphonylation and aging process leads to irreversible AChE inhibition, results in accumulation of excess ACh at the synaptic clefts, and causes neuromuscular paralysis. By employing Born-Oppenheimer ab initio QM/MM molecular dynamics simulations with umbrella sampling, a state-of-the-art approach to simulate enzyme reactions, we have characterized the aging mechanism of soman phosphonylated AChE and determined its free energy profile. This aging reaction starts with the scission of the O2-Cα bond, which is followed by methyl migration, and results in a tertiary carbenium intermediate. At the transition state, the scissile O2-Cα bond is already cleaved with an average O-C distance of 3.2 ± 0.3 Å and the migrating methyl group is shared between Cα and Cβ carbons with C-C distances of 1.9 ± 0.1 and 1.8 ± 0.1 Å, respectively. The negatively charged phosphonate group is stabilized by a salt bridge with the imidazole ring of the catalytic histidine. A major product of aging, 2,3-dimethyl-2-butanol can be formed swiftly by the reaction of a water molecule. Our characterized mechanism and simulation results provide new detailed insights into this important biochemical process." @default.
- W2017108174 created "2016-06-24" @default.
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- W2017108174 creator A5046726965 @default.
- W2017108174 creator A5055772937 @default.
- W2017108174 creator A5063629758 @default.
- W2017108174 date "2012-09-28" @default.
- W2017108174 modified "2023-10-16" @default.
- W2017108174 title "Aging Mechanism of Soman Inhibited Acetylcholinesterase" @default.
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- W2017108174 doi "https://doi.org/10.1021/jp307790v" @default.
- W2017108174 hasPubMedCentralId "https://www.ncbi.nlm.nih.gov/pmc/articles/3475498" @default.
- W2017108174 hasPubMedId "https://pubmed.ncbi.nlm.nih.gov/22984913" @default.
- W2017108174 hasPublicationYear "2012" @default.