title: Hinge-bending motions in the pore domain of a bacterial voltage-gated sodium channel.
abstract: Computational methods and experimental data are used to provide structural models for NaChBac, the homo-tetrameric voltage-gated sodium channel from the bacterium Bacillus halodurans, with a closed and partially open pore domain. Molecular dynamic (MD) simulations on membrane-bound homo-tetrameric NaChBac structures, each comprising six helical transmembrane segments (labeled S1 through S6), reveal that the shape of the lumen, which is defined by the bundle of four alpha-helical S6 segments, is modulated by hinge bending motions around the S6 glycine residues. Mutation of these glycine residues into proline and alanine affects, respectively, the structure and conformational flexibility of the S6 bundle. In the closed channel conformation, a cluster of stacked phenylalanine residues from the four S6 helices hinders diffusion of water molecules and Na(+) ions. Activation of the voltage sensor domains causes destabilization of the aforementioned cluster of phenylalanines, leading to a more open structure. The conformational change involving the phenylalanine cluster promotes a kink in S6, suggesting that channel gating likely results from the combined action of hinge-bending motions of the S6 bundle and concerted reorientation of the aromatic phenylalanine side-chains.
authors.affiliation: Department of Neuroscience and Graduate Program in Cell and Developmental Biology, Thomas Jefferson University, Philadelphia, PA 19107, USA.
authors.forename: Annika F
authors.initials: AF
authors.lastname: Barber
authors.forename: Vincenzo
authors.initials: V
authors.lastname: Carnevale
authors.forename: S G
authors.initials: SG
authors.lastname: Raju
authors.forename: Cristiano
authors.initials: C
authors.lastname: Amaral
authors.forename: Werner
authors.initials: W
authors.lastname: Treptow
authors.forename: Michael L
authors.initials: ML
authors.lastname: Klein
mesh_terms: D001407:Bacillus / Q000378:metabolism; D001426:Bacterial Proteins / Q000378:metabolism; D001703:Biophysics / Q000379:methods; D005998:Glycine / Q000737:chemistry; D015640:Ion Channel Gating / Q000502:physiology; D007477:Ions; D008564:Membrane Potentials; D008958:Models, Molecular; D008968:Molecular Conformation; D056004:Molecular Dynamics Simulation; D009038:Motion; D010649:Phenylalanine / Q000737:chemistry; D011487:Protein Conformation; D017433:Protein Structure, Secondary; D017434:Protein Structure, Tertiary; D012964:Sodium / Q000737:chemistry; D015222:Sodium Channels / Q000378:metabolism*; D013997:Time Factors; D061566:Voltage-Gated Sodium Channels / Q000737:chemistry*
chemical_list: D001426:Bacterial Proteins; D007477:Ions; D015222:Sodium Channels; D061566:Voltage-Gated Sodium Channels; D010649:Phenylalanine; D012964:Sodium; D005998:Glycine