title: Membrane tension, lipid adaptation, conformational changes, and energetics in MscL gating.
abstract: This study aims to explore gating mechanisms of mechanosensitive channels in terms of membrane tension, membrane adaptation, protein conformation, and energetics. The large conductance mechanosensitive channel from Mycobacterium tuberculosis (Tb-MscL) is used as a model system; Tb-MscL acts as a safety valve by releasing small osmolytes through the channel opening under extreme hypoosmotic conditions. Based on the assumption that the channel gating involves tilting of the transmembrane (TM) helices, we have performed free energy simulations of Tb-MscL as a function of TM helix tilt angle in a dimyristoylphosphatidylcholine bilayer. Based on the change in system dimensions, TM helix tilting is shown to be essentially equivalent to applying an excess surface tension to the membrane, causing channel expansion, lipid adaptation, and membrane thinning. Such equivalence is further corroborated by the observation that the free energy cost of Tb-MscL channel expansion is comparable to the work done by the excess surface tension. Tb-MscL TM helix tilting results in an expanded water-conducting channel of an outer dimension similar to the proposed fully open MscL structure. The free energy decomposition indicates a possible expansion mechanism in which tilting and expanding of TM2 facilitates the iris-like motion of TM1, producing an expanded Tb-MscL.
authors.affiliation: Department of Molecular Biosciences and Center for Bioinformatics, The University of Kansas, Lawrence, Kansas, USA.
authors.forename: Huan
authors.initials: H
authors.lastname: Rui
authors.forename: Ritesh
authors.initials: R
authors.lastname: Kumar
authors.forename: Wonpil
authors.initials: W
authors.lastname: Im
mesh_terms: D001426:Bacterial Proteins / Q000737:chemistry* / Q000378:metabolism*; D002462:Cell Membrane / Q000737:chemistry / Q000378:metabolism*; D015640:Ion Channel Gating; D007473:Ion Channels / Q000737:chemistry* / Q000378:metabolism*; D008051:Lipid Bilayers / Q000737:chemistry / Q000378:metabolism*; D056004:Molecular Dynamics Simulation; D009169:Mycobacterium tuberculosis; D020836:Protein Structure, Quaternary; D017433:Protein Structure, Secondary; D013500:Surface Tension; D013816:Thermodynamics
chemical_list: D001426:Bacterial Proteins; D007473:Ion Channels; D008051:Lipid Bilayers; C116377:Tb-MscL protein, Mycobacterium tuberculosis