BINDING OF TACRINE AND 6-CHLOROTACRINE BY ACETYLCHOLINESTERASE

Multiconfiguration thermodynamic integration was used to determine the relative binding strength oftacrine and 6-chlorotacrine by Torpedo ca lifornica acetylcholinesterase. 6-Chloro-tacrine appears to be bound s tronger by 0.7 +/- 0.4 kcal/mol than unsubstituted tacrine when the ac tive site triad residue His-440 is deprotonated. This result is in exc ellent agreement with experimental inhibition data on electric eel ace tylcholinesterase. Electrostatic Poisson-Boltzmann calculations confir m that order of binding strength, resulting in Delta G 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 chl orination is mainly responsible for the increased attraction potential between protonated inhibitor molecule and adjacent aromatic groups of Phe-330 and Trp-84. (C) 1996 John wiley & Sons, Inc.