Molecular dynamics simulations of wild-type and mutant forms of the Mycobacterium tuberculosis MscL channel

The crystal structure of the Mycobacterium tuberculosis homolog of the bact erial mechanosensitive channel of large conductance (Tb-MscL) provides a un ique opportunity to consider mechanosensitive signal transduction at the at omic 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 mu tants, V21A and Q51E. The wild-type Tb-MscL trajectory gives insight into r egions of relative structural stability and instability in the channel stru cture. Channel mutations led to observable changes in the trajectories, suc h as an alteration of intersubunit interactions in the Q51E mutant. In addi tion, interesting patterns of protein-lipid interactions, such as hydrogen bonding, arose in the simulations. These and other observations from the si mulations are relevant to previous and ongoing experimental studies focusin g on characterization of the channel.