Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
. 2008 Sep 25;175(1-3):196-9.
doi: 10.1016/j.cbi.2008.04.044. Epub 2008 May 7.

Acetylcholinesterase: mechanisms of covalent inhibition of H447I mutant determined by computational analyses

Y H Cheng  1 , X L Cheng, Z Radić, J A McCammon
Affiliations

Acetylcholinesterase: mechanisms of covalent inhibition of H447I mutant determined by computational analyses

Y H Cheng et al. Chem Biol Interact. .

Abstract

The reaction mechanisms of two inhibitor TFK(+) and TFK(0) binding to H447I mutant mouse acetylcholinesterase (mAChE) have been investigated by using a combined ab initio quantum mechanical/molecular mechanical (QM/MM) approach and classical molecular dynamics (MD) simulations. TFK(+) binding to the H447I mutant may proceed with a different reaction mechanism from the wild-type. A water molecule takes over the role of His447 and participates in the bond breaking and forming as a "charge relayer". Unlike in the wild-type mAChE case, Glu334, a conserved residue from the catalytic triad, acts as a catalytic base in the reaction. The calculated energy barrier for this reaction is about 8kcal/mol. These predictions await experimental verification. In the case of the neutral ligand TFK(0), however, multiple MD simulations on the TFK(0)/H447I complex reveal that none of the water molecules can be retained in the active site as a "catalytic" water. Taken together our computational studies confirm that TFK(0) is almost inactive in the H447I mutant, and also provide detailed mechanistic insights into the experimental observations.

PubMed Disclaimer

Figures

Figure 1
Figure 1
(a) The acylation mechanism in the wild-type AChE enzyme; (b) The chemical structures of TFK+ and TFK0.
Figure 2
Figure 2
The “water” triad in the active site of the six [M·T+] models. The values of the distances in Å are averaged among six models.
Figure 3
Figure 3
Illustration of the reaction coordinate used for the H447I mutant and TFK+ reaction, which is dOγ−Hγ+dOw−H −dOγ−C −dOw−Hγ−dH−Oδ.
See this image and copyright information in PMC

References

    1. Rosenberry TL. Acetylcholinesterase. Adv. Enzymol. Relat. Areas Mol. Biol. 1975;43:103–218. - PubMed
    1. Schumacher M, Camp S, Maulet Y, Newton M, Macpheequigley K, Taylor SS, Friedmann T, Taylor P. Primary structure of acetylcholinesterase - implications for regulation and function. Fed. Proc. 1986;45:2976–2981. - PubMed
    1. Taylor P. The Pharmacological Basis of Therapeutics. New York: MacMillan; 1985.
    1. Contestabile A, Fila T, Bartesaghi R, Contestabile A, Ciani E. Choline acetyltransferase activity at different ages in brain of ts65dn mice, an animal model for down's syndrome and related neurodegenerative diseases. J. Neurochem. 2006;97:515–526. - PubMed
    1. Piazzi L, Rampa A, Bisi A, Gobbi S, Belluti F, Cavalli A, Bartolini M, Andrisano V, Valenti P, Recanatini M. 3-(4-{[benzyl(methyl)amino]methyl}-phenyl)-6,7-dimethoxy-2h-2-chromenone (ap2238) inhibits both acetylcholinesterase and acetylcholinesterase-induced beta-amyloid aggregation: a dual function lead for alzheimer's disease therapy. J. Med. Chem. 2003;46:2279–2282. - PubMed

Publication types

Substances

LinkOut - more resources