title: Molecular dynamics simulations of wild-type and mutant forms of the Mycobacterium tuberculosis MscL channel.
abstract: The crystal structure of the Mycobacterium tuberculosis homolog of the bacterial mechanosensitive channel of large conductance (Tb-MscL) provides a unique opportunity to consider mechanosensitive signal transduction at the atomic level. Molecular dynamics simulations of the Tb-MscL channel embedded in an explicit lipid bilayer and of its C-terminal helical bundle alone in aqueous solvent were performed. C-terminal calculations imply that although the helix bundle structure is relatively unstable at physiological pH, it may have been stabilized under low pH conditions such as those used in the crystallization of the channel. Specific mutations to the C-terminal region, which cause a similar conservation of the crystal structure conformation, have also been identified. Full channel simulations were performed for the wild-type channel and two experimentally characterized gain-of-function mutants, V21A and Q51E. The wild-type Tb-MscL trajectory gives insight into regions of relative structural stability and instability in the channel structure. Channel mutations led to observable changes in the trajectories, such as an alteration of intersubunit interactions in the Q51E mutant. In addition, interesting patterns of protein-lipid interactions, such as hydrogen bonding, arose in the simulations. These and other observations from the simulations are relevant to previous and ongoing experimental studies focusing on characterization of the channel.
authors.affiliation: Division of Chemistry and Chemical Engineering, California Institute of Technology, Pasadena, California 91125, USA.
authors.forename: D E
authors.initials: DE
authors.lastname: Elmore
authors.forename: D A
authors.initials: DA
authors.lastname: Dougherty
mesh_terms: D019943:Amino Acid Substitution; D001426:Bacterial Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D003198:Computer Simulation; D029968:Escherichia coli Proteins; D006860:Hydrogen Bonding; D006863:Hydrogen-Ion Concentration; D007473:Ion Channels / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism*; D008051:Lipid Bilayers / Q000737:chemistry / Q000378:metabolism; D008563:Membrane Lipids / Q000378:metabolism; D008958:Models, Molecular; D016297:Mutagenesis, Site-Directed; D009154:Mutation; D009169:Mycobacterium tuberculosis / Q000737:chemistry* / Q000235:genetics; D020836:Protein Structure, Quaternary; D017433:Protein Structure, Secondary; D021122:Protein Subunits; D055672:Static Electricity; D013816:Thermodynamics; D014867:Water / Q000737:chemistry / Q000378:metabolism
chemical_list: D001426:Bacterial Proteins; D029968:Escherichia coli Proteins; D007473:Ion Channels; D008051:Lipid Bilayers; D008563:Membrane Lipids; C086596:MscL protein, E coli; D021122:Protein Subunits; D014867:Water