title: Reaction pathway and free-energy barrier for reactivation of dimethylphosphoryl-inhibited human acetylcholinesterase.
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.
authors.affiliation: Key Laboratory of Pesticide and Chemical Biology of Ministry of Education, College of Chemistry, Central China Normal University, Wuhan 430079, People's Republic of China.
authors.forename: Junjun
authors.initials: J
authors.lastname: Liu
authors.forename: Yingkai
authors.initials: Y
authors.lastname: Zhang
authors.forename: Chang-Guo
authors.initials: CG
authors.lastname: Zhan
mesh_terms: D000110:Acetylcholinesterase; D002801:Cholinesterase Reactivators / Q000737:chemistry*; D006801:Humans; D009943:Organophosphorus Compounds / Q000737:chemistry*; D011789:Quantum Theory; D013816:Thermodynamics; D014867:Water / Q000737:chemistry
chemical_list: D002801:Cholinesterase Reactivators; D009943:Organophosphorus Compounds; D014867:Water; D000110:Acetylcholinesterase; C007477:dimethyl phosphate