High-throughput simulations reveal membrane-mediated effects of alcohols on MscL gating
Journal Article
·
· Journal of the American Chemical Society
- Univ. of Groningen, Groningen (The Netherlands)
- Univ. of Groningen, Groningen (The Netherlands); Lawrence Livermore National Lab. (LLNL), Livermore, CA (United States)
The mechanosensitive channels of large conductance (MscL) are bacterial membrane proteins that serve as last resort emergency release valves in case of severe osmotic downshock. Sensing bilayer tension, MscL channels are sensitive to changes in the bilayer environment and are, therefore, an ideal test case for exploring membrane protein coupling. Here, we use high-throughput coarse-grained molecular dynamics simulations to characterize MscL gating kinetics in different bilayer environments under the influence of alcohols. We performed over five hundred simulations to obtain sufficient statistics to reveal the subtle effects of changes in the membrane environment on MscL gating. MscL opening times were found to increase with the addition of the straight-chain alcohols ethanol, octanol, and to some extent dodecanol but not with hexadecanol. Increasing concentration of octanol increased the impeding effect, but only up to 10–20 mol %. Our in silico predictions were experimentally confirmed using reconstituted MscL in a liposomal fluorescent efflux assay. Our combined data reveal that the effect of alcohols on MscL gating arises not through specific binding sites but through a combination of the alcohol-induced changes to a number of bilayer properties and their alteration of the MscL–bilayer interface. Finally, our work provides a key example of how extensive molecular simulations can be used to predict the functional modification of membrane proteins by subtle changes in their bilayer environment.
- Research Organization:
- Lawrence Livermore National Laboratory (LLNL), Livermore, CA (United States)
- Sponsoring Organization:
- USDOE
- Grant/Contract Number:
- AC52-07NA27344
- OSTI ID:
- 1346131
- Report Number(s):
- LLNL-JRNL--715277
- Journal Information:
- Journal of the American Chemical Society, Journal Name: Journal of the American Chemical Society Journal Issue: 7 Vol. 139; ISSN 0002-7863
- Publisher:
- American Chemical Society (ACS)Copyright Statement
- Country of Publication:
- United States
- Language:
- English
Emerging Diversity in Lipid–Protein Interactions
|
journal | January 2019 |
Connecting Structure–Property and Structure–Function Relationships across the Disciplines of Chemistry and Biology: Exploring Student Perceptions
|
journal | June 2018 |
Unraveling the molecular principles by which ceramides commit cells to death
|
journal | August 2019 |
Alcohol Interactions with Lipid Bilayers
|
journal | November 2017 |
A Practical View of the Martini Force Field
|
book | January 2019 |
Ceramides bind VDAC2 to trigger mitochondrial apoptosis
|
journal | April 2019 |
Similar Records
Force transduction and lipid binding in MscL: A continuum-molecular approach
Elucidating a role for the cytoplasmic domain in the Mycobacterium tuberculosis mechanosensitive channel of large conductance
Journal Article
·
Sun Nov 30 19:00:00 EST 2014
· PLoS ONE
·
OSTI ID:1214236
Elucidating a role for the cytoplasmic domain in the Mycobacterium tuberculosis mechanosensitive channel of large conductance
Journal Article
·
Sun Sep 30 20:00:00 EDT 2018
· Scientific Reports
·
OSTI ID:1624426