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Volume 272, Number 37, Issue of September 12, 1997 pp. 23265-23277
©1997 by The American Society for Biochemistry and Molecular Biology, Inc.

Electrostatic Influence on the Kinetics of Ligand Binding to Acetylcholinesterase
DISTINCTIONS BETWEEN ACTIVE CENTER LIGANDS AND FASCICULIN

(Received for publication, April 16, 1997, and in revised form, June 19, 1997)

Zoran Radic' Dagger , Paul D. Kirchhoff § , Daniel M. Quinn , J. Andrew McCammon Dagger § and Palmer Taylor Dagger

From the Departments of Dagger  Pharmacology and of § Chemistry and Biochemistry, University of California San Diego, La Jolla, California 92093-0636 and the  Department of Chemistry, University of Iowa, Iowa City, Iowa 52242

To explore the role that surface and active center charges play in electrostatic attraction of ligands to the active center gorge of acetylcholinesterase (AChE), and the influence of charge on the reactive orientation of the ligand, we have studied the kinetics of association of cationic and neutral ligands with the active center and peripheral site of AChE. Electrostatic influences were reduced by sequential mutations of six surface anionic residues outside of the active center gorge (Glu-84, Glu-91, Asp-280, Asp-283, Glu-292, and Asp-372) and three residues within the active center gorge (Asp-74 at the rim and Glu-202 and Glu-450 at the base). The peripheral site ligand, fasciculin 2 (FAS2), a peptide of 6.5 kDa with a net charge of +4, shows a marked enhancement of rate of association with reduction in ionic strength, and this ionic strength dependence can be markedly reduced by progressive neutralization of surface and active center gorge anionic residues. By contrast, neutralization of surface residues only has a modest influence on the rate of cationic m-trimethylammoniotrifluoroacetophenone (TFK+) association with the active serine, whereas neutralization of residues in the active center gorge has a marked influence on the rate but with little change in the ionic strength dependence. Brownian dynamics calculations for approach of a small cationic ligand to the entrance of the gorge show the influence of individual charges to be in quantitative accord with that found for the surface residues. Anionic residues in the gorge may help to orient the ligand for reaction or to trap the ligand. Bound FAS2 on AChE not only reduces the rate of TFK+ reaction with the active center but inverts the ionic strength dependence for the cationic TFK+ association with AChE. Hence it appears that TFK+ must traverse an electrostatic barrier at the gorge entry imparted by the bound FAS2 with its net charge of +4.


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