NDLI: Electrostatic Steering at Acetylcholine Binding Sites

Content Provider	PubMed Central
Author	Meltzer, Robert H. Thompson, Errol Soman, Kizhake V. Song, Xing-zhi Ebalunode, Jerry O. Wensel, Theodore G. Briggs, James M. Pedersen, Steen E.
Copyright Year	2006
Abstract	The electrostatic environments near the acetylcholine binding sites on the nicotinic acetylcholine receptor (nAChR) and acetylcholinesterase were measured by diffusion-enhanced fluorescence energy transfer (DEFET) to determine the influence of long-range electrostatic interactions on ligand binding kinetics and net binding energy. Changes in DEFET from variously charged Tb3+-chelates revealed net potentials of −20 mV at the nAChR agonist sites and −14 mV at the entrance to the AChE active site, in physiological ionic strength conditions. The potential at the α δ-binding site of the nAChR was determined independently in the presence of d-tubocurarine to be −14 mV; the calculated potential at the α γ-site was approximately threefold stronger than at the α δ-site. By determining the local potential in increasing ionic strength, Debye-Hückel theory predicted that the potentials near the nAChR agonist binding sites are constituted by one to three charges in close proximity to the binding site. Examination of the binding kinetics of the fluorescent acetylcholine analog dansyl-C6-choline at ionic strengths from 12.5 to 400 mM revealed a twofold decrease in association rate. Debye-Hückel analysis of the kinetics revealed a similar charge distribution as seen by changes in the potentials. To determine whether the experimentally determined potentials are reflected by continuum electrostatics calculations, solutions to the nonlinear Poisson-Boltzmann equation were used to compute the potentials expected from DEFET measurements from high-resolution models of the nAChR and AChE. These calculations are in good agreement with the DEFET measurements for AChE and for the α γ-site of the nAChR. We conclude that long-range electrostatic interactions contribute −0.3 and −1 kcal/mol to the binding energy at the nAChR α δ- and α γ-sites due to an increase in association rates.
Related Links	http://dx.doi.org/10.1529/biophysj.106.081463
Starting Page	1302
File Format	PDF
ISSN	15420086
e-ISSN	15420086
Journal	Biophysical Journal
Issue Number	4
Volume Number	91
Language	English
Publisher	Biophysical Society
Publisher Date	2006-08-15
Access Restriction	Open
Rights Holder	Biophysical Society
Subject Keyword	Research in Higher Education
Content Type	Text
Resource Type	Article
Subject	Biophysics

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