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. 2011 Feb 10;115(5):1315-22.
doi: 10.1021/jp110709a. Epub 2010 Dec 22.

Reaction pathway and free energy profile for butyrylcholinesterase-catalyzed hydrolysis of acetylcholine

Xi Chen  1 , Lei Fang, Junjun Liu, Chang-Guo Zhan
Affiliations

Reaction pathway and free energy profile for butyrylcholinesterase-catalyzed hydrolysis of acetylcholine

Xi Chen et al. J Phys Chem B. .

Abstract

A catalytic mechanism for the butyrylcholinesterase (BChE)-catalyzed hydrolysis of acetylcholine (ACh) has been studied by performing pseudobond first-principles quantum mechanical/molecular mechanical-free energy calculations on both acylation and deacylation of BChE. It has been shown that the acylation with ACh includes two reaction steps, including nucleophilic attack on the carbonyl carbon of ACh and dissociation of choline ester. The deacylation stage includes nucleophilic attack of a water molecule on the carboxyl carbon of the substrate and dissociation between the carboxyl carbon of the substrate and the hydroxyl oxygen of the Ser198 side chain. Notably, despite the fact that acetylcholinesterase (AChE) and BChE are very similar enzymes, the acylation of BChE with ACh is rate-determining, which is remarkably different from the AChE-catalyzed hydrolysis of ACh, in which the deacylation is rate-determining. The computational prediction is consistent with available experimental kinetic data. The overall free energy barrier calculated for BChE-catalyzed hydrolysis of ACh is 13.8 kcal/mol, which is in good agreement with the experimentally derived activation free energy of 13.3 kcal/mol.

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Figures

Figure 1
Figure 1
Key internuclear distances (D1 to D5) vs simulation time in the MD-simulated BChE-ACh complex.
Figure 2
Figure 2
Key states for the acylation reaction stage of BChE-catalyzed ACh hydrolysis. The geometries were optimized at the QM/MM(B3LYP/6-31G*:AMBER) level. The key distances in the figure are in Å. Carbon, oxygen, nitrogen, and hydrogen atoms are colored in greed, red, blue, and white, respectively. The backbone of the protein is rendered in orange. The QM atoms are represented as balls and sticks and the surrounding residues are rendered as sticks or lines. The figures below are represented using the same method.
Figure 3
Figure 3
Key states for the deacylation reaction of BChE-catalyzed ACh hydrolysis. The geometries were optimized at QM/MM(B3LYP/6-31G*:AMBER) level. See caption of Figure 2 for the color codes for different types of atoms.
Figure 4
Figure 4
Free energy profiles for the acylation and deacylation stages of BChE-catalyzed hydrolysis of ACh. The relative free energies were determined by the QM/MM-FE calculations at the MP2/6-31+G*:AMBER level, excluding the zero-point and thermal corrections for the QM system. Values in the parenthesis are relative free energies including the zero-point and thermal corrections for the QM subsystem.
Scheme 1
Scheme 1
Proposed catalytic reaction pathway for BChE-catalyzed hydrolysis of acetylcholine. Atoms colored in blue are treated by QM method in the pseudobond first-principles QM/MM calculations. Three boundary carbon atoms (Cα or Cβ) are treated with the improved pseudobond parameters . All other atoms belong to the MM subsystem.
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