title: New insights of membrane environment effects on MscL channel mechanics from theoretical approaches.
abstract: The prokaryotic mechanosensitive channel of large conductance (MscL) is a remarkable integral membrane protein. During hypo-osmotic shock, it responses to membrane tension through large conformational changes, that lead to an open state of the pore. The structure of the channel from Mycobacterium tuberculosis has been resolved in the closed state. Numerous experiments have attempted to trap the channel in its open state but they did not succeed in obtaining a structure. A gating mechanism has been proposed based on different experimental data but there is no experimental technique available to follow this process in atomic details. In addition, it has been shown that a decrease of the lipid bilayer thickness lowered MscL activation energy and stabilized a structurally distinct closed channel intermediate. Here, we use atomistic molecular dynamics simulations to investigate the effect of the lipid bilayer thinning on our model of the structure of the Escherichia coli. We thoroughly analyze simulations of the channel embedded in two pre-equilibrated membranes differing by their hydrophobic tail length (DMPE and POPE). The MscL structure remains stable in POPE, whereas a distinct structural state is obtained in DMPE in response to hydrophobic mismatch. This latter is obtained by tilts and kinks of the transmembrane helices, leading to a widening and a diminution of the channel height. Part of these motions is guided by a competition between solvent and lipids for the interaction with the periplasmic loops. We finally conduct a principal component analysis of the simulation and compare anharmonic motions with harmonic ones, previously obtained from a coarse-grained normal mode analysis performed on the same structural model. Significant similarities exist between low-frequency harmonic motions and those observed with essential dynamics in DMPE. In summary, change in membrane thickness permits to accelerate the conformational changes involved in the mechanics of the E. coli channel, providing a closed structural intermediate en route to the open state. These results give clues for better understanding why the channel activation energy is lowered in a thinner membrane.
authors.affiliation: EBGM, INSERM UMR-S 726, Université Paris Diderot, 2 Place Jussieu, Case 7113, 75251 Paris cedex 05, France.
authors.forename: Gaëlle
authors.initials: G
authors.lastname: Debret
authors.forename: Hélène
authors.initials: H
authors.lastname: Valadié
authors.forename: Andreas Maximilian
authors.initials: AM
authors.lastname: Stadler
authors.forename: Catherine
authors.initials: C
authors.lastname: Etchebest
mesh_terms: D003198:Computer Simulation; D004777:Environment; D029968:Escherichia coli Proteins / Q000737:chemistry*; D007473:Ion Channels / Q000737:chemistry*; D008051:Lipid Bilayers / Q000737:chemistry*; D040542:Mechanotransduction, Cellular; D008956:Models, Chemical; D010714:Phosphatidylethanolamines / Q000737:chemistry; D025341:Principal Component Analysis; D011487:Protein Conformation; D017433:Protein Structure, Secondary
chemical_list: D029968:Escherichia coli Proteins; D007473:Ion Channels; D008051:Lipid Bilayers; C086596:MscL protein, E coli; D010714:Phosphatidylethanolamines; C057561:1-palmitoyl-2-oleoylphosphatidylethanolamine; C018525:1,2-dimyristoylphosphatidylethanolamine