Paper Report for: Liu_2009_J.Phys.Chem.B_113_16226
Reference
Title: Reaction pathway and free-energy barrier for reactivation of dimethylphosphoryl-inhibited human acetylcholinesterase Liu J, Zhang Y, Zhan CG Ref: J Phys Chem B, 113:16226, 2009 : PubMed
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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Liu J, Zhang Y, Zhan CG (2009) Reaction pathway and free-energy barrier for reactivation of dimethylphosphoryl-inhibited human acetylcholinesterase J Phys Chem B113: 16226-36
Liu J, Zhang Y, Zhan CG (2009) J Phys Chem B113: 16226-36