Binding of tacrine and 6-chlorotacrine by acetylcholinesterase

S. T. Wlodek, J. Antosiewicz, J. A. McCammon, T. P. Straatsma, M. K. Gilson, J. M. Briggs, C. Humblet, J. L. Sussman

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60 Scopus citations

Abstract

Multiconfiguration thermodynamic integration was used to determine the relative binding strength of tacrine and 6-chlorotacrine by Torpedo californica acetylcholinesterase. 6-Chlorotacrine appears to be bound stronger by 0.7 ± 0.4 kcal/mol than unsubstituted tacrine when the active site triad residue His-440 is deprotonated. This result is in excellent agreement with experimental inhibition data on electric eel acetylcholinesterase. Electrostatic Poisson-Boltzmann calculations confirm that order of binding strength, resulting in ΔG of binding of-2.9 and -3.3 kcal/mol for tacrine and chlorotacrine, respectively, and suggest inhibitor binding does not occur when His-440 is charged. Our results suggest that electron density redistribution upon tacrine chlorination is mainly responsible for the increased attraction potential between protonated inhibitor molecule and adjacent aromatic groups of Phe-330 and Trp-84.

Original languageEnglish
Pages (from-to)109-117
Number of pages9
JournalBiopolymers
Volume38
Issue number1
DOIs
StatePublished - 1996
Externally publishedYes

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