ArticleThe journal of physical chemistry. B2010
Catalytic reaction mechanism of acetylcholinesterase determined by Born-Oppenheimer ab initio QM/MM molecular dynamics simulations.
Article in The journal of physical chemistry. B, 2010. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 45 papers.
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Who cites it
45 citing papers in PubMed, 138 citations in OpenAlex.
- Recent Advances in Pyrazole-Based Cholinesterase Inhibitors: Medicinal Chemistry Perspectives from 2020 to 2025.Pharmaceuticals (Basel, Switzerland) · 2026Review
- The Pharmacokinetic Properties of Veterinary Antiparasitic Drugs in the Context of Human Pregnancy-An In Silico Study.International journal of molecular sciences · 2026Article
- A copper-mediated Fenton-like dual-mode optical sensor for sensitive determination of acetylcholinesterase activity in biological fluids.RSC advances · 2026Article
- Structure-Activity Relationships, Molecular Mechanisms, and Ecotoxicological Evaluation Underlying Nucleoside-Mediated Antifouling Activity.Biomolecules · 2026Article
- Oxidative Stress and Neurotoxicity Biomarkers in Fish Toxicology.Antioxidants (Basel, Switzerland) · 2025Review
- Mechanistic Insights into Enhanced Reactivation of Organophosphate-Inhibited Enzymes by Methyl-Substituted 2-Pralidoxime Analogs.The journal of physical chemistry. B · 2025Article
- Transdermal delivery of resveratrol loaded solid lipid nanoparticle as a microneedle patch: a novel approach for the treatment of Parkinson's disease.Drug delivery and translational research · 2025Article
- Resveratrol-Based Carbamates as Selective Butyrylcholinesterase Inhibitors: Design, Synthesis, Computational Study and Biometal Complexation Capability.Molecules (Basel, Switzerland) · 2025Article
- Novel Dual Acetyl- and Butyrylcholinesterase Inhibitors Based on the Pyridyl-Pyridazine Moiety for the Potential Treatment of Alzheimer's Disease.Pharmaceuticals (Basel, Switzerland) · 2024Article
- Current Insights of Nanocarrier-Mediated Gene Therapeutics to Treat Potential Impairment of Amyloid Beta Protein and Tau Protein in Alzheimer's Disease.Molecular neurobiology · 2024Review
- The reaction mechanism of the Ideonella sakaiensis PETase enzyme.Communications chemistry · 2024Article
- Article
- Pharmacotherapy Evolution in Alzheimer's Disease: Current Framework and Relevant Directions.Cells · 2022Review
- Application of Computational Biology and Artificial Intelligence in Drug Design.International journal of molecular sciences · 2022Review
- Improved machine learning scoring functions for identification of Electrophorus electricus's acetylcholinesterase inhibitors.Molecular diversity · 2022Article
- Synthesis, in vitro biological evaluation and molecular modelling of new 2-chloro-3-hydrazinopyrazine derivatives as potent acetylcholinesterase inhibitors on PC12 cells.BMC chemistry · 2022Article
- A Comprehensive Review of Cholinesterase Modeling and Simulation.Biomolecules · 2021Review
- Anticholinesterase Activity of Eight Medicinal Plant Species:Evidence-based complementary and alternative medicine : eCAM · 2021Article
- Characterization and engineering of a two-enzyme system for plastics depolymerization.Proceedings of the National Academy of Sciences of the United States of America · 2020Article
- Structural insights into the putative bacterial acetylcholinesterase ChoE and its substrate inhibition mechanism.The Journal of biological chemistry · 2020Article
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Authors and funding
3 authors at 1 institution in 1 country.
Funding
Abstract
Acetylcholinesterase (AChE) is a remarkably efficient serine hydrolase responsible for the termination of impulse signaling at cholinergic synapses. By employing Born-Oppenheimer molecular dynamics simulations with a B3LYP/6-31G(d) QM/MM potential and the umbrella sampling method, we have characterized its complete catalytic reaction mechanism for hydrolyzing neurotransmitter acetylcholine (ACh) and determined its multistep free-energy reaction profiles for the first time. In both acylation and deacylation reaction stages, the first step involves the nucleophilic attack on the carbonyl carbon, with the triad His447 serving as the general base, and leads to a tetrahedral covalent intermediate stabilized by the oxyanion hole. From the intermediate to the product, the orientation of the His447 ring needs to be adjusted very slightly, and then, the proton transfers from His447 to the product, and the break of the scissile bond happens spontaneously. For the three-pronged oxyanion hole, it only makes two hydrogen bonds with the carbonyl oxygen at either the initial reactant or the final product state, but the third hydrogen bond is formed and stable at all transition and intermediate states during the catalytic process. At the intermediate state of the acylation reaction, a short and low-barrier hydrogen bond (LBHB) is found to be formed between two catalytic triad residues His447 and Glu334, and the spontaneous proton transfer between two residues has been observed. However, it is only about 1-2 kcal/mol stronger than the normal hydrogen bond. In comparison with previous theoretical investigations of the AChE catalytic mechanism, our current study clearly demonstrates the power and advantages of employing Born-Oppenheimer ab initio QM/MM MD simulations in characterizing enzyme reaction mechanisms.
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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.