ArticleThe journal of physical chemistry. B2012
Aging mechanism of soman inhibited acetylcholinesterase.
Article in The journal of physical chemistry. B, 2012. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 22 papers.
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Who cites it
22 citing papers in PubMed, 63 citations in OpenAlex.
- Computational Chemistry and Toxicology of Phosphonate Esters of Alkyl Acetoacetates, an Unexplored Class of V-Agents.Current issues in molecular biology · 2026Article
- Acetylcholinesterase: Structure, dynamics, and interactions with organophosphorus compounds.Protein science : a publication of the Protein Society · 2025Review
- Article
- Antidotes in Clinical Toxicology-Critical Review.Toxics · 2023Review
- Chemical, Physical, and Toxicological Properties of V-Agents.International journal of molecular sciences · 2023Review
- What do we currently know about Novichoks? The state of the art.Archives of toxicology · 2023Review
- Article
- Midazolam-Resistant Seizures and Brain Injury after Acute Intoxication of Diisopropylfluorophosphate, an Organophosphate Pesticide and Surrogate for Nerve Agents.The Journal of pharmacology and experimental therapeutics · 2018Article
- Full Protection Against Soman-Induced Seizures and Brain Damage by LY293558 and Caramiphen Combination Treatment in Adult Rats.Neurotoxicity research · 2018Article
- New therapeutic approaches and novel alternatives for organophosphate toxicity.Toxicology letters · 2018Article
- Comparing the Antiseizure and Neuroprotective Efficacy of LY293558, Diazepam, Caramiphen, and LY293558-Caramiphen Combination against Soman in a Rat Model Relevant to the Pediatric Population.The Journal of pharmacology and experimental therapeutics · 2018Article
- Computational Studies on Acetylcholinesterases.Molecules (Basel, Switzerland) · 2017Review
- The M1 Muscarinic Receptor Antagonist VU0255035 Delays the Development of Status Epilepticus after Organophosphate Exposure and Prevents Hyperexcitability in the Basolateral Amygdala.The Journal of pharmacology and experimental therapeutics · 2017Article
- Long-term neuropathological and behavioral impairments after exposure to nerve agents.Annals of the New York Academy of Sciences · 2016Review
- Thiol versus hydroxamate as zinc binding group in HDAC inhibition: An ab initio QM/MM molecular dynamics study.Journal of computational chemistry · 2015Article
- A fluorogenic aryl fluorosulfate for intraorganellar transthyretin imaging in living cells and in Caenorhabditis elegans.Journal of the American Chemical Society · 2015Article
- A rat model of nerve agent exposure applicable to the pediatric population: The anticonvulsant efficacies of atropine and GluK1 antagonists.Toxicology and applied pharmacology · 2015Article
- A wrench in the works of human acetylcholinesterase: soman induced conformational changes revealed by molecular dynamics simulations.PloS one · 2015Article
- How is acetylcholinesterase phosphonylated by soman? An ab initio QM/MM molecular dynamics study.The journal of physical chemistry. A · 2014Article
- Article
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Authors and funding
5 authors at 2 institutions in 2 countries.
Funding
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.
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