title: Homology modeling and molecular dynamics simulations of transmembrane domain structure of human neuronal nicotinic acetylcholine receptor.
abstract: A three-dimensional model of the transmembrane domain of a neuronal-type nicotinic acetylcholine receptor (nAChR), (alpha4)2(beta2)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 alpha4-E266 with its adjacent beta2-K260 was observed in the neuronal-type channel during the course of the molecular-dynamics simulations. The narrowest region, with a pore radius of approximately 2 A formed by the salt-bridges, does not seem to be the restriction site for a continuous water passage. Instead, two hydrophobic rings, formed by alpha4-V259, alpha4-L263, and the homologous residues in the beta2-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 (alpha4)2(beta2)3 nAChR channel, and may lead to a better understanding of the structures, dynamics, and functions of this family of ion channels.
authors.affiliation: Department of Anesthesiology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA.
authors.forename: Alexander C
authors.initials: AC
authors.lastname: Saladino
authors.forename: Yan
authors.initials: Y
authors.lastname: Xu
authors.forename: Pei
authors.initials: P
authors.lastname: Tang
mesh_terms: D000595:Amino Acid Sequence; D003198:Computer Simulation; D004058:Diffusion; D004134:Dimyristoylphosphatidylcholine / Q000737:chemistry; D008051:Lipid Bilayers / Q000737:chemistry*; D008956:Models, Chemical; D008958:Models, Molecular; D008969:Molecular Sequence Data; D009038:Motion; D018482:Muscle, Skeletal / Q000737:chemistry / Q000378:metabolism; D009474:Neurons / Q000737:chemistry* / Q000378:metabolism*; D016062:Porosity; D011487:Protein Conformation; D017434:Protein Structure, Tertiary; D011978:Receptors, Nicotinic / Q000032:analysis / Q000737:chemistry* / Q000648:ultrastructure; D020539:Sequence Analysis, Protein / Q000379:methods*; D017386:Sequence Homology, Amino Acid; D013329:Structure-Activity Relationship; D014867:Water / Q000737:chemistry
chemical_list: D008051:Lipid Bilayers; D011978:Receptors, Nicotinic; D014867:Water; D004134:Dimyristoylphosphatidylcholine