The pore domain of the nicotinic acetylcholine receptor: molecular modeling, pore dimensions, and electrostatics

Abstract

The pore domain of the nicotinic acetylcholine receptor has been modeled as a bundle of five kinked M2 helices. Models were generated via molecular dynamics simulations incorporating restraints derived from 9-A resolution cryoelectron microscopy data (Unwin, 1993; 1995), and from mutagenesis data that identify channel-lining side chains. Thus, these models conform to current experimental data but will require revision as higher resolution data become available. Models of the open and closed states of a homopentameric alpha 7 pore are compared. The minimum radius of the closed-state model is less than 2 A; the minimum radius of the open-state models is approximately 6 A. It is suggested that the presence of "bound" water molecules within the pore may reduce the effective minimum radii below these values by up to approximately 3 A. Poisson-Boltzmann calculations are used to obtain a first approximation to the potential energy of a monovalent cation as it moves along the pore axis. The differences in electrostatic potential energy profiles between the open-state models of alpha 7 and of a mutant of alpha 7 are consistent with the experimentally observed change in ion selectivity from cationic to anionic. Models of the open state of the heteropentameric Torpedo nicotinic acetylcholine receptor pore domain are also described. Relatively small differences in pore radius and electrostatic potential energy profiles are seen when the Torpedo and alpha 7 models are compared.

Bundles Consisting of Extended Transmembrane Segments of Vpu from HIV-1: Computer Simulations and Conductance Measurements

“…The conception of hydrophilic residues lining the pore is based on experimental findings in the pore-lining helices of the nicotinic acetylcholine receptor (nAChR) (38)(39)(40)(41). Computational studies have used these findings to generate not only equivalent bundles of M2 from nAChR (31,32) but also bundles of the TM domain of the influenza A channel protein M2 (33) and the channel protein NB from influenza B (34). However, recent studies also show that the positioning of tryptophans toward the center of the pore can result in a model representing a stable "closed" structure (21,24,42).…”

Allosteric modifiers of neuronal nicotinic acetylcholine receptors: New methods, new opportunities

“…There have been several proposed molecular models of the transmembrane domain of the a7 nAChR 37,38 and cryo-electron microscopy images have been used to develop models of the Torpedo marmorata nAChR (abdg nAChR). 39 We have recently reported a model of the central lumen of the a3b4 nAChR, which can be used to describe the binding and function of NCIs to this receptor.…”

Structure and dynamics of the pore-lining helix of the nicotinic receptor: MD simulations in water, lipid bilayers, and transbilayer bundles

“…Molecular modelling studies restrained by cryoelectron microscopy data indicate that the M2 helices are kinked. 7,8 The kink is thought to be in the vicinity of a Leu residue that is conserved between subunits and between nicotinic receptors from different species. This Leu has been suggested to play a role in the gating mechanism of the channel.…”

“…This Leu has been suggested to play a role in the gating mechanism of the channel. It is suggested that the helix kink may correspond to a molecular hinge, 3,8 enabling changes in conformation and packing of the M2 helices in response to binding of neurotransmitter and resulting in a switch from a closed (i.e., ion impermeable) to an open (i.e., ion permeable) channel.…”