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Mechanosensitive channels: insights from continuum-based simulations.

ABSTRACT: Mechanotransduction plays an important role in regulating cell functions and it is an active topic of research in biophysics. Despite recent advances in experimental and numerical techniques, the intrinsic multiscale nature imposes tremendous challenges for revealing the working mechanisms of mechanosensitive channels. Recently, a continuum-mechanics-based hierarchical modeling and simulation framework has been established and applied to study the mechanical responses and gating behaviors of a prototypical mechanosensitive channel, the mechanosensitive channel of large conductance (MscL) in bacteria Escherichia coli (E. coli), from which several putative gating mechanisms have been tested and new insights are deduced. This article reviews these latest findings using the continuum mechanics framework and suggests possible improvements for future simulation studies. This computationally efficient and versatile continuum-mechanics-based protocol is poised to make contributions to the study of a variety of mechanobiology problems.

SUBMITTER: Tang Y

PROVIDER: S-EPMC2651832 | biostudies-literature | 2008

REPOSITORIES: biostudies-literature

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Mechanosensitive channels: insights from continuum-based simulations.

Tang Yuye Y Yoo Jejoong J Yethiraj Arun A Cui Qiang Q Chen Xi X

Cell biochemistry and biophysics 20080912 1

Mechanotransduction plays an important role in regulating cell functions and it is an active topic of research in biophysics. Despite recent advances in experimental and numerical techniques, the intrinsic multiscale nature imposes tremendous challenges for revealing the working mechanisms of mechanosensitive channels. Recently, a continuum-mechanics-based hierarchical modeling and simulation framework has been established and applied to study the mechanical responses and gating behaviors of a p ...[more]

PMID: 18787764

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Project description:GsMTx4 is a spider venom peptide that inhibits cationic mechanosensitive channels (MSCs). It has six lysine residues that have been proposed to affect membrane binding. We synthesized six analogs with single lysine-to-glutamate substitutions and tested them against Piezo1 channels in outside-out patches and independently measured lipid binding. Four analogs had ?20% lower efficacy than the wild-type (WT) peptide. The equilibrium constants calculated from the rates of inhibition and washout did not correlate with the changes in inhibition. The lipid association strength of the WT GsMTx4 and the analogs was determined by tryptophan autofluorescence quenching and isothermal calorimetry with membrane vesicles and showed no significant differences in binding energy. Tryptophan fluorescence-quenching assays showed that both WT and analog peptides bound superficially near the lipid-water interface, although analogs penetrated deeper. Peptide-lipid association, as a function of lipid surface pressure, was investigated in Langmuir monolayers. The peptides occupied a large fraction of the expanded monolayer area, but that fraction was reduced by peptide expulsion as the pressure approached the monolayer-bilayer equivalence pressure. Analogs with compromised efficacy had pressure-area isotherms with steeper slopes in this region, suggesting tighter peptide association. The pressure-dependent redistribution of peptide between "deep" and "shallow" binding modes was supported by molecular dynamics (MD) simulations of the peptide-monolayer system under different area constraints. These data suggest a model placing GsMTx4 at the membrane surface, where it is stabilized by the lysines, and occupying a small fraction of the surface area in unstressed membranes. When applied tension reduces lateral pressure in the lipids, the peptides penetrate deeper acting as "area reservoirs" leading to partial relaxation of the outer monolayer, thereby reducing the effective magnitude of stimulus acting on the MSC gate.

Dataset Information

Mechanosensitive channels: insights from continuum-based simulations.

Publications

Mechanosensitive channels: insights from continuum-based simulations.

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