ArticleThe journal of physical chemistry. A2014
How is acetylcholinesterase phosphonylated by soman? An ab initio QM/MM molecular dynamics study.
Article in The journal of physical chemistry. A, 2014. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 18 papers.
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Who cites it
18 citing papers in PubMed, 36 citations in OpenAlex.
- Article
- Neuroprotective Effects of Senecio brasiliensis Extract Against Chlorpyrifos-Induced Neurotoxicity and Oxidative Stress in Drosophila melanogaster.Basic & clinical pharmacology & toxicology · 2026Article
- Current review on inducible nitric oxide synthase and Src tyrosine kinase inhibitors as disease-modifiers in preclinical models of epilepsy.Histology and histopathology · 2026Review
- Chlorpyrifos and Chlorpyrifos-Oxon: A Widening Spectrum of Toxicity.International journal of molecular sciences · 2026Review
- Article
- Article
- Dynamic interchange between two protonation states is characteristic of active sites of cholinesterases.Protein science : a publication of the Protein Society · 2024Article
- Assessing the Risks of Pesticide Exposure: Implications for Endocrine Disruption and Male Fertility.International journal of molecular sciences · 2024Review
- Novichok Nerve Agents as Inhibitors of Acetylcholinesterase-In Silico Study of Their Non-Covalent Binding Affinity.Molecules (Basel, Switzerland) · 2024Article
- Mechanisms of Organophosphate Toxicity and the Role of Acetylcholinesterase Inhibition.Toxics · 2023Review
- Molecular Modeling Studies on the Multistep Reactivation Process of Organophosphate-Inhibited Acetylcholinesterase and Butyrylcholinesterase.Biomolecules · 2021Article
- Soman (GD) Rat Model to Mimic Civilian Exposure to Nerve Agent: Mortality, Video-EEG BasedFrontiers in cellular neuroscience · 2021Article
- Understanding the enzyme-ligand complex: insights from all-atom simulations of butyrylcholinesterase inhibition.Journal of biomolecular structure & dynamics · 2020Article
- Computational Studies on Acetylcholinesterases.Molecules (Basel, Switzerland) · 2017Review
- Article
- The Cytoplasmic and Periplasmic Expression Levels and Folding of Organophosphorus Hydrolase Enzyme in Escherichia coli.Jundishapur journal of microbiology · 2015Article
- Thiol versus hydroxamate as zinc binding group in HDAC inhibition: An ab initio QM/MM molecular dynamics study.Journal of computational chemistry · 2015Article
- A wrench in the works of human acetylcholinesterase: soman induced conformational changes revealed by molecular dynamics simulations.PloS one · 2015Article
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Authors and funding
2 authors at 1 institution in 2 countries.
Funding
Abstract
Acetylcholinesterase (AChE) is a crucial enzyme in the cholinergic nerve system that hydrolyzes acetylcholine (ACh) and terminates synaptic signals by reducing the effective concentration of ACh in the synaptic clefts. Organophosphate compounds irreversibly inhibit AChEs, leading to irreparable damage to nerve cells. 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 covalent inhibition mechanism between AChE and the nerve toxin soman and determined its free energy profile for the first time. Our results indicate that phosphonylation of the catalytic serine by soman employs an addition-elimination mechanism, which is highly associative and stepwise: in the initial addition step, which is also rate-limiting, His440 acts as a general base to facilitate the nucleophilic attack of Ser200 on the soman's phosphorus atom to form a trigonal bipyrimidal pentacovalent intermediate; in the subsequent elimination step, Try121 of the catalytic gorge stabilizes the leaving fluorine atom prior to its dissociation from the active site. Together with our previous characterization of the aging mechanism of soman inhibited AChE, our simulations have revealed detailed molecular mechanistic insights into the damaging function of the nerve agent soman.
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