Binding of tacrine and 6-chlorotacrine by acetylcholinesterase.

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 deltaG 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 pronated inhibitor molecule and adjacent aromatic groups of Phe-330 and Trp-84.

journal_name

Biopolymers

journal_title

Biopolymers

authors

Wlodek ST,Antosiewicz J,McCammon JA,Straatsma TP,Gilson MK,Briggs JM,Humblet C,Sussman JL

doi

10.1002/(sici)1097-0282(199601)38:1<109::aid-bip9>

subject

Has Abstract

pub_date

1996-01-01 00:00:00

pages

109-17

issue

1

eissn

0006-3525

issn

1097-0282

pii

10.1002/(SICI)1097-0282(199601)38:1<109::AID-BIP9>

journal_volume

38

pub_type

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