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

¹ University of Pittsburgh School of Medicine

^* To whom correspondence should be addressed. E-mail: tangp{at}anes.upmc.edu.

Submitted on September 23, 2004
Revised on November 7, 2004
Accepted on 18 November 2004

	Abstract

A three-dimensional model of transmembrane (TM) domain of a neuronal-type nicotinic acetylcholine receptor (nAChR), (4)2(2)3, was constructed from a homology structure of the muscle-type nAChR recently determined by the cryo-electron microscopy. The neuronal channel model was embedded in a fully hydrated DMPC lipid bilayer, and molecular dynamics (MD) 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 4-E266 with its adjacent 2-K260 was observed in the neuronal-type channel during the course of the MD 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 4-V259, 4-L263, and the homologous residues in the 2 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 (4)2(2)3 nAChR channel, and may lead to a better understanding of the structures, dynamics, and functions of this family of ion channels.

Key Words: Acetylcholine receptors, Cys-loop receptors, Homology modeling, MD simulations, Neuronal nAChR, ion channels

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