Catalytic reaction mechanism of acetylcholinesterase determined by born-oppenheimer Ab initio QM/MM molecular dynamics simulations

Yanzi Zhou, Shenglong Wang, Yingkai Zhang

Research output: Contribution to journalArticle

Abstract

Acetylcholinesterase (AChE) is a remarkably efficient serine hydrolase responsible for the termination of impulse signaling at cholinergic synapses. By employing Born-Oppenheimer molecular dynamics simulations with a B3LYP/6-31G(d) QM/MM potential and the umbrella sampling method, we have characterized its complete catalytic reaction mechanism for hydrolyzing neurotransmitter acetylcholine (ACh) and determined its multistep free-energy reaction profiles for the first time. In both acylation and deacylation reaction stages, the first step involves the nucleophilic attack on the carbonyl carbon, with the triad His447 serving as the general base, and leads to a tetrahedral covalent intermediate stabilized by the oxyanion hole. From the intermediate to the product, the orientation of the His447 ring needs to be adjusted very slightly, and then, the proton transfers from His447 to the product, and the break of the scissile bond happens spontaneously. For the three-pronged oxyanion hole, it only makes two hydrogen bonds with the carbonyl oxygen at either the initial reactant or the final product state, but the third hydrogen bond is formed and stable at all transition and intermediate states during the catalytic process. At the intermediate state of the acylation reaction, a short and low-barrier hydrogen bond (LBHB) is found to be formed between two catalytic triad residues His447 and Glu334, and the spontaneous proton transfer between two residues has been observed. However, it is only about 1-2 kcal/mol stronger than the normal hydrogen bond. In comparison with previous theoretical investigations of the AChE catalytic mechanism, our current study clearly demonstrates the power and advantages of employing Born-Oppenheimer ab initio QM/MM MD simulations in characterizing enzyme reaction mechanisms.

Original languageEnglish (US)
Pages (from-to)8817-8825
Number of pages9
JournalJournal of Physical Chemistry B
Volume114
Issue number26
DOIs
StatePublished - Jul 8 2010

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Molecular Dynamics Simulation
Acetylcholinesterase
Molecular dynamics
Hydrogen
Hydrogen bonds
molecular dynamics
Acylation
Proton transfer
hydrogen bonds
Computer simulation
acylation
Protons
simulation
Hydrolases
products
cholinergics
acetylcholine
neurotransmitters
synapses
Synapses

ASJC Scopus subject areas

  • Physical and Theoretical Chemistry
  • Materials Chemistry
  • Surfaces, Coatings and Films
  • Medicine(all)

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Catalytic reaction mechanism of acetylcholinesterase determined by born-oppenheimer Ab initio QM/MM molecular dynamics simulations. / Zhou, Yanzi; Wang, Shenglong; Zhang, Yingkai.

In: Journal of Physical Chemistry B, Vol. 114, No. 26, 08.07.2010, p. 8817-8825.

Research output: Contribution to journalArticle

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