Reaction pathway and free-energy barrier for reactivation of dimethylphosphoryl-inhibited human acetylcholinesterase

Junjun Liu, Yingkai Zhang, Chang Guo Zhan

Research output: Contribution to journalArticlepeer-review


The dephosphorylation/reactivation mechanism and the corresponding free-energy profile of the dimethylphosphoryl-inhibited conjugate of human acetylcholinesterase (AChE) has been studied by performing firstprinciples 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.

Original languageEnglish (US)
Pages (from-to)16225-16236
Number of pages12
JournalJournal of Physical Chemistry B
Issue number50
StatePublished - Dec 17 2009

ASJC Scopus subject areas

  • Physical and Theoretical Chemistry
  • Surfaces, Coatings and Films
  • Materials Chemistry


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