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Title: High-throughput simulations reveal membrane-mediated effects of alcohols on MscL gating

Abstract

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 howmore » extensive molecular simulations can be used to predict the functional modification of membrane proteins by subtle changes in their bilayer environment.« less

Authors:
 [1];  [1];  [1];  [1];  [1];  [1];  [1];  [1]; ORCiD logo [2]
  1. Univ. of Groningen, Groningen (The Netherlands)
  2. Univ. of Groningen, Groningen (The Netherlands); Lawrence Livermore National Lab. (LLNL), Livermore, CA (United States)
Publication Date:
Research Org.:
Lawrence Livermore National Laboratory (LLNL), Livermore, CA (United States)
Sponsoring Org.:
USDOE
OSTI Identifier:
1346131
Report Number(s):
LLNL-JRNL-715277
Journal ID: ISSN 0002-7863
Grant/Contract Number:  
AC52-07NA27344
Resource Type:
Journal Article: Accepted Manuscript
Journal Name:
Journal of the American Chemical Society
Additional Journal Information:
Journal Volume: 139; Journal Issue: 7; Journal ID: ISSN 0002-7863
Publisher:
American Chemical Society (ACS)
Country of Publication:
United States
Language:
English
Subject:
59 BASIC BIOLOGICAL SCIENCES

Citation Formats

Melo, Manuel N., Arnarez, Clement, Sikkema, Hendrik, Kumar, Neeraj, Walko, Martin, Berendsen, Herman J. C., Kocer, Armagan, Marrink, Siewert J., and Ingolfsson, Helgi I. High-throughput simulations reveal membrane-mediated effects of alcohols on MscL gating. United States: N. p., 2017. Web. doi:10.1021/jacs.6b11091.
Melo, Manuel N., Arnarez, Clement, Sikkema, Hendrik, Kumar, Neeraj, Walko, Martin, Berendsen, Herman J. C., Kocer, Armagan, Marrink, Siewert J., & Ingolfsson, Helgi I. High-throughput simulations reveal membrane-mediated effects of alcohols on MscL gating. United States. https://doi.org/10.1021/jacs.6b11091
Melo, Manuel N., Arnarez, Clement, Sikkema, Hendrik, Kumar, Neeraj, Walko, Martin, Berendsen, Herman J. C., Kocer, Armagan, Marrink, Siewert J., and Ingolfsson, Helgi I. 2017. "High-throughput simulations reveal membrane-mediated effects of alcohols on MscL gating". United States. https://doi.org/10.1021/jacs.6b11091. https://www.osti.gov/servlets/purl/1346131.
@article{osti_1346131,
title = {High-throughput simulations reveal membrane-mediated effects of alcohols on MscL gating},
author = {Melo, Manuel N. and Arnarez, Clement and Sikkema, Hendrik and Kumar, Neeraj and Walko, Martin and Berendsen, Herman J. C. and Kocer, Armagan and Marrink, Siewert J. and Ingolfsson, Helgi I.},
abstractNote = {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.},
doi = {10.1021/jacs.6b11091},
url = {https://www.osti.gov/biblio/1346131}, journal = {Journal of the American Chemical Society},
issn = {0002-7863},
number = 7,
volume = 139,
place = {United States},
year = {Thu Jan 26 00:00:00 EST 2017},
month = {Thu Jan 26 00:00:00 EST 2017}
}

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Cited by: 30 works
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The influence of n-alkanols on the capacity per unit area of planar lipid bilayers
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Protein modulation of lipids, and vice-versa, in membranes
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The effect of aliphatic alcohols on fluid bilayers in unilamellar DOPC vesicles — A small-angle neutron scattering and molecular dynamics study
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Packing properties of 1-alkanols and alkanes in a phospholipid membrane
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Modulation of KvAP Unitary Conductance and Gating by 1-Alkanols and Other Surface Active Agents
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Protein Shape Change Has a Major Effect on the Gating Energy of a Mechanosensitive Channel
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Membrane Tension, Lipid Adaptation, Conformational Changes, and Energetics in MscL Gating
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Alcohol's Effects on Lipid Bilayer Properties
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Sensing and Responding to Membrane Tension: The Bacterial MscL Channel as a Model System
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The Nanomechanical Properties of Lipid Membranes are Significantly Influenced by the Presence of Ethanol
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Sidekick for Membrane Simulations: Automated Ensemble Molecular Dynamics Simulations of Transmembrane Helices
journal, April 2014


High-Throughput Simulations of Dimer and Trimer Assembly of Membrane Proteins. The DAFT Approach
journal, March 2015


GROMACS 4:  Algorithms for Highly Efficient, Load-Balanced, and Scalable Molecular Simulation
journal, February 2008


The MARTINI Coarse-Grained Force Field: Extension to Proteins
journal, April 2008


Coarse Grained Model for Semiquantitative Lipid Simulations
journal, January 2004


The MARTINI Force Field:  Coarse Grained Model for Biomolecular Simulations
journal, July 2007


Influence of Ethanol on Lipid Membranes:  From Lateral Pressure Profiles to Dynamics and Partitioning
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Mechanosensitive ion channels of E. coli activated by amphipaths
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A large-conductance mechanosensitive channel in E. coli encoded by mscL alone
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Physical principles underlying the transduction of bilayer deformation forces during mechanosensitive channel gating
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Pressure-sensitive ion channel in Escherichia coli.
journal, April 1987


Perspectives on How to Drug an Ion Channel
journal, April 2008


The activation mode of the mechanosensitive ion channel, MscL, by lysophosphatidylcholine differs from tension‐induced gating
journal, June 2014


Lipid bilayer regulation of membrane protein function: gramicidin channels as molecular force probes
journal, July 2009


Bilayer Thickness and Membrane Protein Function: An Energetic Perspective
journal, June 2007


Molecular Basis of Mechanotransduction in Living Cells
journal, April 2001


Computational ‘microscopy’ of cellular membranes
journal, January 2016


Force Transduction and Lipid Binding in MscL: A Continuum-Molecular Approach
journal, December 2014


Lipid Bilayer Pressure Profiles and Mechanosensitive Channel Gating
journal, June 2004


How Alcohol Chain-Length and Concentration Modulate Hydrogen Bond Formation in a Lipid Bilayer
journal, April 2007


Gating of the Mechanosensitive Channel Protein MscL: The Interplay of Membrane and Protein
journal, May 2008


Mechanosensitive Membrane Channels in Action
journal, April 2008


The Influence of 1-Alkanols and External Pressure on the Lateral Pressure Profiles of Lipid Bilayers
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Works referencing / citing this record:

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