ArticlePloS one2015
A wrench in the works of human acetylcholinesterase: soman induced conformational changes revealed by molecular dynamics simulations.
Article in PloS one, 2015. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 14 papers.
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14 citing papers in PubMed, 36 citations in OpenAlex.
- Click-chemistry-derived oxime library reveals efficient reactivators of nerve agent-inhibited butyrylcholinesterase suitable for pseudo-catalytic bioscavenging.Archives of toxicology · 2025Article
- Enzyme Dynamics Determine the Potency and Selectivity of Inhibitors Targeting Disease-Transmitting Mosquitoes.ACS infectious diseases · 2024Article
- In silico analysis of the use of solanine derivatives as a treatment for Alzheimer's disease.Heliyon · 2024Article
- Inhibitory Action of Omega-3 and Omega-6 Fatty Acids Alpha-Linolenic, Arachidonic and Linoleic acid on Human Erythrocyte Acetylcholinesterase.The protein journal · 2023Article
- Broad-Spectrum Antidote Discovery by Untangling the Reactivation Mechanism of Nerve-Agent-Inhibited Acetylcholinesterase.Chemistry (Weinheim an der Bergstrasse, Germany) · 2022Article
- A MajorPlants (Basel, Switzerland) · 2022Article
- Development of a CNS-permeable reactivator for nerve agent exposure: an iterative, multi-disciplinary approach.Scientific reports · 2021Article
- A Comprehensive Review of Cholinesterase Modeling and Simulation.Biomolecules · 2021Review
- Sulfonylurea Class of Antidiabetic Drugs Inhibit Acetylcholinesterase Activity: Unexplored Auxiliary Pharmacological Benefit toward Alzheimer's Disease.ACS pharmacology & translational science · 2021Article
- Structure-Antifouling Activity Relationship and Molecular Targets of Bio-Inspired(thio)xanthones.Biomolecules · 2020Article
- Identification of new allosteric sites and modulators of AChE through computational and experimental tools.Journal of enzyme inhibition and medicinal chemistry · 2018Article
- Computational Studies on Acetylcholinesterases.Molecules (Basel, Switzerland) · 2017Review
- Gorge Motions of Acetylcholinesterase Revealed by Microsecond Molecular Dynamics Simulations.Scientific reports · 2017Article
- Potential acetylcholinesterase inhibitors: molecular docking, molecular dynamics, and in silico prediction.Journal of molecular modeling · 2017Article
Corrections and comments
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Authors and funding
6 authors at 2 institutions in 2 countries.
Funding
No grant is acknowledged in the PubMed record.
Abstract
Irreversible inactivation of human acetylcholinesterase (hAChE) by organophosphorous pesticides (OPs) and chemical weapon agents (CWA) has severe morbidity and mortality consequences. We present data from quantum mechanics/molecular mechanics (QM/MM) and 80 classical molecular dynamics (MD) simulations of the apo and soman-adducted forms of hAChE to investigate the effects on the dynamics and protein structure when the catalytic Serine 203 is phosphonylated. We find that the soman phosphonylation of the active site Ser203 follows a water assisted addition-elimination mechanism with the elimination of the fluoride ion being the highest energy barrier at 6.5 kcal/mole. We observe soman-dependent changes in backbone and sidechain motions compared to the apo form of the protein. These alterations restrict the soman-adducted hAChE to a structural state that is primed for the soman adduct to be cleaved and removed from the active site. The altered motions and resulting structures provide alternative pathways into and out of the hAChE active site. In the soman-adducted protein both side and back door pathways are viable for soman adduct access. Correlation analysis of the apo and soman adducted MD trajectories shows that the correlation of gorge entrance and back door motion is disrupted when hAChE is adducted. This supports the hypothesis that substrate and product can use two different pathways as entry and exit sites in the apo form of the protein. These alternative pathways have important implications for the rational design of medical countermeasures.
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