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Originally published as Biophys J. BioFAST on December 1, 2004.
doi:10.1529/biophysj.104.053421
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Biophysical Journal 88:1009-1017 (2005)
© 2005 The Biophysical Society

Homology Modeling and Molecular Dynamics Simulations of Transmembrane Domain Structure of Human Neuronal Nicotinic Acetylcholine Receptor

Alexander C. Saladino *, Yan Xu * {dagger} and Pei Tang * {dagger}

Departments of * Anesthesiology and {dagger} Pharmacology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania

Correspondence: Address reprint requests to Professor Pei Tang, PhD, W-1357 Biomedical Science Tower, University of Pittsburgh School of Medicine, Pittsburgh, PA 15261. Tel.: 412-383-9798; Fax: 412-648-9587; E-mail: tangp{at}anes.upmc.edu.

A three-dimensional model of the transmembrane domain of a neuronal-type nicotinic acetylcholine receptor (nAChR), ({alpha}4)2(ß2)3, was constructed from a homology structure of the muscle-type nAChR recently determined by cryo-electron microscopy. The neuronal channel model was embedded in a fully hydrated DMPC lipid bilayer, and molecular-dynamics simulations were performed for 5 ns. A comparative analysis of the neuronal- versus muscle-type nAChR models revealed many conserved pore-lining residues, but an important difference was found near the periplasmic mouth of the pore. A flickering salt-bridge of {alpha}4-E266 with its adjacent ß2-K260 was observed in the neuronal-type channel during the course of the molecular-dynamics simulations. The narrowest region, with a pore radius of ~2 Å formed by the salt-bridges, does not seem to be the restriction site for a continuous water passage. Instead, two hydrophobic rings, formed by {alpha}4-V259, {alpha}4-L263, and the homologous residues in the ß2-subunits, act as the gates for water flow, even though the region has a slightly larger pore radius. The model offers new insight into the water transport across the ({alpha}4)2(ß2)3 nAChR channel, and may lead to a better understanding of the structures, dynamics, and functions of this family of ion channels.




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