Role of the catalytic triad and oxyanion hole in acetylcholinesterase catalysis: An ab initio QM/MM study

Yingkai Zhang, Jeremy Kua, J. Andrew McCammon

Research output: Contribution to journalArticle

Abstract

The initial step of the acylation reaction catalyzed by acetylcholinesterase (ACHE) has been studied by a combined ab initio quantum mechanical/molecular mechanical (QM/MM) approach. The reaction proceeds through the nucleophilic addition of the Ser203 O to the carbonyl C of acetylcholine, and the reaction is facilitated by simultaneous proton transfer from Ser203 to His447. The calculated potential energy barrier at the MP2(6-31+G*) QM/MM level is 10.5 kcal/mol, consistent with the experimental reaction rate. The third residue of the catalytic triad, Glu334, is found to be essential in stabilizing the transition state through electrostatic interactions. The oxyanion hole, formed by peptidic NH groups from Gly121, Gly122, and Ala204, is also found to play an important role in catalysis. Our calculations indicate that, in the AChE-ACh Michaelis complex, only two hydrogen bonds are formed between the carbonyl oxygen of ACh and the peptidic NH groups of Gly121 and Gly122. As the reaction proceeds, the distance between the carbonyl oxygen of ACh and NH group of Ala204 becomes smaller, and the third hydrogen bond is formed both in the transition state and in the tetrahedral intermediate.

Original languageEnglish (US)
Pages (from-to)10572-10577
Number of pages6
JournalJournal of the American Chemical Society
Volume124
Issue number35
DOIs
StatePublished - Sep 4 2002

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Acetylcholinesterase
Catalysis
Hydrogen
Hydrogen bonds
Oxygen
Acylation
Proton transfer
Energy barriers
Coulomb interactions
Potential energy
Static Electricity
Acetylcholine
Reaction rates
Protons

ASJC Scopus subject areas

  • Chemistry(all)

Cite this

Role of the catalytic triad and oxyanion hole in acetylcholinesterase catalysis : An ab initio QM/MM study. / Zhang, Yingkai; Kua, Jeremy; McCammon, J. Andrew.

In: Journal of the American Chemical Society, Vol. 124, No. 35, 04.09.2002, p. 10572-10577.

Research output: Contribution to journalArticle

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