ArticleThe journal of physical chemistry. B2009
Reaction pathway and free-energy barrier for reactivation of dimethylphosphoryl-inhibited human acetylcholinesterase.
Article in The journal of physical chemistry. B, 2009. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 20 papers.
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Who cites it
20 citing papers in PubMed.
- Study on Spontaneous Reactivation and Aging of Acetylcholinesterase Inhibited by Paraoxon and Malaoxon in Ten Species.International journal of molecular sciences · 2023Article
- Application of Computational Biology and Artificial Intelligence in Drug Design.International journal of molecular sciences · 2022Review
- In silico Studies on the Interaction between Mpro and PLpro From SARS-CoV-2 and Ebselen, its Metabolites and Derivatives.Molecular informatics · 2021Article
- Catalytic Mechanisms for Cofactor-Free Oxidase-Catalyzed Reactions: Reaction Pathways of Uricase-Catalyzed Oxidation and Hydration of Uric Acid.ACS catalysis · 2017Article
- Quantum mechanics implementation in drug-design workflows: does it really help?Drug design, development and therapy · 2017Review
- Reaction Pathway for Cocaine Hydrolase-Catalyzed Hydrolysis of (+)-Cocaine.Theoretical chemistry accounts · 2016Article
- Fundamental reaction pathway and free energy profile of proteasome inhibition by syringolin A (SylA).Organic & biomolecular chemistry · 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
- Binding free energies for nicotine analogs inhibiting cytochrome P450 2A6 by a combined use of molecular dynamics simulations and QM/MM-PBSA calculations.Bioorganic & medicinal chemistry · 2014Article
- Fundamental reaction pathway for peptide metabolism by proteasome: insights from first-principles quantum mechanical/molecular mechanical free energy calculations.The journal of physical chemistry. B · 2013Article
- Fundamental reaction pathway and free energy profile for butyrylcholinesterase-catalyzed hydrolysis of heroin.Biochemistry · 2013Article
- Reaction pathway and free energy profile for papain-catalyzed hydrolysis of N-acetyl-Phe-Gly 4-nitroanilide.Biochemistry · 2013Article
- Article
- Aging mechanism of soman inhibited acetylcholinesterase.The journal of physical chemistry. B · 2012Article
- Fundamental reaction pathway and free energy profile for inhibition of proteasome by Epoxomicin.Journal of the American Chemical Society · 2012Article
- Reaction pathway and free energy profiles for butyrylcholinesterase-catalyzed hydrolysis of acetylthiocholine.Biochemistry · 2012Article
- Fundamental reaction pathway and free energy profile for hydrolysis of intracellular second messenger adenosine 3',5'-cyclic monophosphate (cAMP) catalyzed by phosphodiesterase-4.The journal of physical chemistry. B · 2011Article
- Reaction pathway and free energy profile for butyrylcholinesterase-catalyzed hydrolysis of acetylcholine.The journal of physical chemistry. B · 2011Article
- Molecular basis of the selectivity of the immunoproteasome catalytic subunit LMP2-specific inhibitor revealed by molecular modeling and dynamics simulations.The journal of physical chemistry. B · 2010Article
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3 authors.
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Abstract
The dephosphorylation/reactivation mechanism and the corresponding free-energy profile of the dimethylphosphoryl-inhibited conjugate of human acetylcholinesterase (AChE) has been studied by performing first-principles quantum mechanical/molecular mechanical free-energy (QM/MM-FE) calculations. On the basis of the QM/MM-FE results, for the favorable reaction pathway, the entire dephosphorylation/reactivation process consists of three reaction steps, including the nucleophilic water attack on the P atom, the spatial reorganization of the dimethylphosphoryl group, and the dissociation between the dimethylphosphoryl group and Ser203 of AChE. The overall free-energy barrier for the entire dephosphorylation/reactivation reaction is found to be the free-energy change from the initial reactant to the transition state associated with the spatial reorganization step, and the calculated overall free-energy barrier (20.1 to 23.5 kcal/mol) is reasonably close to the experimentally derived activation free energy of 22.3 kcal/mol. In addition, key amino acid residues and their specific roles in the reaction process have been identified.
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