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

Melo, Manuel N.; Arnarez, Clement; Sikkema, Hendrik; Kumar, Neeraj; Walko, Martin; Berendsen, Herman J. C.; Kocer, Armagan; Marrink, Siewert J.; Ingolfsson, Helgi I.

doi:10.1021/jacs.6b11091

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

Journal Article · Thu Jan 26 00:00:00 EST 2017 · Journal of the American Chemical Society

DOI:https://doi.org/10.1021/jacs.6b11091· OSTI ID:1346131

Melo, Manuel N. ^[1]; Arnarez, Clement ^[1]; Sikkema, Hendrik ^[1]; Kumar, Neeraj ^[1]; Walko, Martin ^[1]; Berendsen, Herman J. C. ^[1]; Kocer, Armagan ^[1]; Marrink, Siewert J. ^[1];

^[2]

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.

View Accepted Manuscript (DOE)

Cite

Export

Save

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, Vol. 139, Issue 7; ISSN 0002-7863

Publisher:: American Chemical Society (ACS)Copyright Statement

Country of Publication:: United States

Language:: English

Citation Metrics:

Cited by: 35 works

Citation information provided by
Web of Science

References (64)

Refinement of the fluid-mosaic model of membrane structure Israelachvili, Jacob N. Biochimica et Biophysica Acta (BBA) - Biomembranes, Vol. 469, Issue 2 https://doi.org/10.1016/0005-2736(77)90185-7	journal	September 1977
Deformation free energy of bilayer membrane and its effect on gramicidin channel lifetime Huang, H. W. Biophysical Journal, Vol. 50, Issue 6 https://doi.org/10.1016/S0006-3495(86)83550-0	journal	December 1986
Bilayer Thickness and Membrane Protein Function: An Energetic Perspective Andersen, Olaf S.; Koeppe, Roger E. Annual Review of Biophysics and Biomolecular Structure, Vol. 36, Issue 1 https://doi.org/10.1146/annurev.biophys.36.040306.132643	journal	June 2007
Perspectives on How to Drug an Ion Channel Andersen, Olaf Sparre Journal of General Physiology, Vol. 131, Issue 5 https://doi.org/10.1085/jgp.200810012	journal	April 2008
Protein modulation of lipids, and vice-versa, in membranes Marsh, Derek Biochimica et Biophysica Acta (BBA) - Biomembranes, Vol. 1778, Issue 7-8 https://doi.org/10.1016/j.bbamem.2008.01.015	journal	July 2008
Lipid bilayer regulation of membrane protein function: gramicidin channels as molecular force probes Lundbæk, Jens A.; Collingwood, Shemille A.; Ingólfsson, Helgi I. Journal of The Royal Society Interface, Vol. 7, Issue 44 https://doi.org/10.1098/rsif.2009.0443	journal	July 2009
Amphiphile regulation of ion channel function by changes in the bilayer spring constant Lundbaek, J. A.; Koeppe, R. E.; Andersen, O. S. Proceedings of the National Academy of Sciences, Vol. 107, Issue 35 https://doi.org/10.1073/pnas.1007455107	journal	August 2010
Pressure-sensitive ion channel in Escherichia coli. Martinac, B.; Buechner, M.; Delcour, A. H. Proceedings of the National Academy of Sciences, Vol. 84, Issue 8 https://doi.org/10.1073/pnas.84.8.2297	journal	April 1987
A large-conductance mechanosensitive channel in E. coli encoded by mscL alone Sukharev, Sergei I.; Blount, Paul; Martinac, Boris Nature, Vol. 368, Issue 6468 https://doi.org/10.1038/368265a0	journal	March 1994
Structure of the MscL Homolog from Mycobacterium tuberculosis: A Gated Mechanosensitive Ion Channel Chang, G.; Spencer, R. H.; Lee, A. T. Science, Vol. 282, Issue 5397 https://doi.org/10.1126/science.282.5397.2220	journal	December 1998
Molecular Basis of Mechanotransduction in Living Cells Hamill, Owen P.; Martinac, Boris Physiological Reviews, Vol. 81, Issue 2 https://doi.org/10.1152/physrev.2001.81.2.685	journal	April 2001
Mechanosensitive channels in bacteria: signs of closure? Booth, Ian R.; Edwards, Michelle D.; Black, Susan Nature Reviews Microbiology, Vol. 5, Issue 6 https://doi.org/10.1038/nrmicro1659	journal	June 2007
Mechanosensitive Channels: What Can They Do and How Do They Do It? Haswell, Elizabeth S.; Phillips, Rob; Rees, Douglas C. Structure, Vol. 19, Issue 10 https://doi.org/10.1016/j.str.2011.09.005	journal	October 2011
Mechanisms of mechanosensing — mechanosensitive channels, function and re-engineering Kocer, Armagan Current Opinion in Chemical Biology, Vol. 29 https://doi.org/10.1016/j.cbpa.2015.10.006	journal	December 2015
Physical principles underlying the transduction of bilayer deformation forces during mechanosensitive channel gating Perozo, Eduardo; Kloda, Anna; Cortes, D. Marien Nature Structural Biology, Vol. 9, Issue 9 https://doi.org/10.1038/nsb827	journal	August 2002
Mechanosensitive ion channels of E. coli activated by amphipaths Martinac, Boris; Adler, Julius; Kung, Ching Nature, Vol. 348, Issue 6298 https://doi.org/10.1038/348261a0	journal	November 1990
The activation mode of the mechanosensitive ion channel, MscL, by lysophosphatidylcholine differs from tension‐induced gating Mukherjee, Nobina; Jose, Mac Donald; Birkner, Jan Peter The FASEB Journal, Vol. 28, Issue 10 https://doi.org/10.1096/fj.14-251579	journal	June 2014
Phytochemicals Perturb Membranes and Promiscuously Alter Protein Function Ingólfsson, Helgi I.; Thakur, Pratima; Herold, Karl F. ACS Chemical Biology, Vol. 9, Issue 8 https://doi.org/10.1021/cb500086e	journal	June 2014
Simulation of MscL Gating in a Bilayer under Stress Colombo, Giorgio; Marrink, Siewert Jan; Mark, Alan E. Biophysical Journal, Vol. 84, Issue 4 https://doi.org/10.1016/S0006-3495(03)75038-3	journal	April 2003
Molecular Dynamics Simulations of Wild-Type and Mutant Forms of the Mycobacterium tuberculosis MscL Channel Elmore, Donald E.; Dougherty, Dennis A. Biophysical Journal, Vol. 81, Issue 3 https://doi.org/10.1016/S0006-3495(01)75791-8	journal	September 2001
Gating of the Mechanosensitive Channel Protein MscL: The Interplay of Membrane and Protein Jeon, Jonggu; Voth, Gregory A. Biophysical Journal, Vol. 94, Issue 9 https://doi.org/10.1529/biophysj.107.109850	journal	May 2008
Membrane Tension, Lipid Adaptation, Conformational Changes, and Energetics in MscL Gating Rui, Huan; Kumar, Ritesh; Im, Wonpil Biophysical Journal, Vol. 101, Issue 3 https://doi.org/10.1016/j.bpj.2011.06.029	journal	August 2011
Force Transduction and Lipid Binding in MscL: A Continuum-Molecular Approach Vanegas, Juan M.; Arroyo, Marino PLoS ONE, Vol. 9, Issue 12 https://doi.org/10.1371/journal.pone.0113947	journal	December 2014
Sidekick for Membrane Simulations: Automated Ensemble Molecular Dynamics Simulations of Transmembrane Helices Hall, Benjamin A.; Halim, Khairul Bariyyah Abd; Buyan, Amanda Journal of Chemical Theory and Computation, Vol. 10, Issue 5 https://doi.org/10.1021/ct500003g	journal	April 2014
The power of coarse graining in biomolecular simulations: The power of coarse graining in biomolecular simulations Ingólfsson, Helgi I.; Lopez, Cesar A.; Uusitalo, Jaakko J. Wiley Interdisciplinary Reviews: Computational Molecular Science, Vol. 4, Issue 3 https://doi.org/10.1002/wcms.1169	journal	August 2013
High-Throughput Simulations of Dimer and Trimer Assembly of Membrane Proteins. The DAFT Approach Wassenaar, Tsjerk A.; Pluhackova, Kristyna; Moussatova, Anastassiia Journal of Chemical Theory and Computation, Vol. 11, Issue 5 https://doi.org/10.1021/ct5010092	journal	March 2015
Computational ‘microscopy’ of cellular membranes Ingólfsson, Helgi I.; Arnarez, Clément; Periole, Xavier Journal of Cell Science, Vol. 129, Issue 2 https://doi.org/10.1242/jcs.176040	journal	January 2016
Perspective on the Martini model Marrink, Siewert J.; Tieleman, D. Peter Chemical Society Reviews, Vol. 42, Issue 16 https://doi.org/10.1039/c3cs60093a	journal	January 2013
Mechanosensitive Membrane Channels in Action Yefimov, Serge; van der Giessen, Erik; Onck, Patrick R. Biophysical Journal, Vol. 94, Issue 8 https://doi.org/10.1529/biophysj.107.119966	journal	April 2008
Release of content through mechano-sensitive gates in pressurized liposomes Louhivuori, M.; Risselada, H. J.; van der Giessen, E. Proceedings of the National Academy of Sciences, Vol. 107, Issue 46 https://doi.org/10.1073/pnas.1001316107	journal	November 2010
Alcohol's Effects on Lipid Bilayer Properties Ingólfsson, Helgi I.; Andersen, Olaf S. Biophysical Journal, Vol. 101, Issue 4 https://doi.org/10.1016/j.bpj.2011.07.013	journal	August 2011
Coarse Grained Model for Semiquantitative Lipid Simulations Marrink, Siewert J.; de Vries, Alex H.; Mark, Alan E. The Journal of Physical Chemistry B, Vol. 108, Issue 2 https://doi.org/10.1021/jp036508g	journal	January 2004
The MARTINI Force Field: Coarse Grained Model for Biomolecular Simulations Marrink, Siewert J.; Risselada, H. Jelger; Yefimov, Serge The Journal of Physical Chemistry B, Vol. 111, Issue 27 https://doi.org/10.1021/jp071097f	journal	July 2007
The MARTINI Coarse-Grained Force Field: Extension to Proteins Monticelli, Luca; Kandasamy, Senthil K.; Periole, Xavier Journal of Chemical Theory and Computation, Vol. 4, Issue 5 https://doi.org/10.1021/ct700324x	journal	April 2008
GROMACS 4: Algorithms for Highly Efficient, Load-Balanced, and Scalable Molecular Simulation Hess, Berk; Kutzner, Carsten; van der Spoel, David Journal of Chemical Theory and Computation, Vol. 4, Issue 3 https://doi.org/10.1021/ct700301q	journal	February 2008
Computational Lipidomics with insane : A Versatile Tool for Generating Custom Membranes for Molecular Simulations Wassenaar, Tsjerk A.; Ingólfsson, Helgi I.; Böckmann, Rainer A. Journal of Chemical Theory and Computation, Vol. 11, Issue 5 https://doi.org/10.1021/acs.jctc.5b00209	journal	April 2015
Molecular dynamics with coupling to an external bath Berendsen, H. J. C.; Postma, J. P. M.; van Gunsteren, W. F. The Journal of Chemical Physics, Vol. 81, Issue 8 https://doi.org/10.1063/1.448118	journal	October 1984
MDAnalysis: A toolkit for the analysis of molecular dynamics simulations Michaud-Agrawal, Naveen; Denning, Elizabeth J.; Woolf, Thomas B. Journal of Computational Chemistry, Vol. 32, Issue 10 https://doi.org/10.1002/jcc.21787	journal	April 2011
MDAnalysis: A Python Package for the Rapid Analysis of Molecular Dynamics Simulations Gowers, Richard; Linke, Max; Barnoud, Jonathan Proceedings of the Python in Science Conference https://doi.org/10.25080/Majora-629e541a-00e	conference	January 2016
Synthesis and utilization of reversible and irreversible light-activated nanovalves derived from the channel protein MscL Koçer, Armağan; Walko, Martin; Feringa, Ben L. Nature Protocols, Vol. 2, Issue 6 https://doi.org/10.1038/nprot.2007.196	journal	May 2007
Mathematical functions for the analysis of luminescence decays with underlying distributions 1. Kohlrausch decay function (stretched exponential) Berberan-Santos, M. N.; Bodunov, E. N.; Valeur, B. Chemical Physics, Vol. 315, Issue 1-2 https://doi.org/10.1016/j.chemphys.2005.04.006	journal	August 2005
Primary Alcohols Modulate the Activation of the G Protein-coupled Receptor Rhodopsin by a Lipid-mediated Mechanism Mitchell, Drake C.; Lawrence, John T. R.; Litman, Burton J. Journal of Biological Chemistry, Vol. 271, Issue 32 https://doi.org/10.1074/jbc.271.32.19033	journal	August 1996
Mutations of -aminobutyric acid and glycine receptors change alcohol cutoff: Evidence for an alcohol receptor? Wick, M. J.; Mihic, S. J.; Ueno, S. Proceedings of the National Academy of Sciences, Vol. 95, Issue 11 https://doi.org/10.1073/pnas.95.11.6504	journal	May 1998
The influence of n-alkanols on the capacity per unit area of planar lipid bilayers Elliott, J. R.; Haydon, D. A. Biochimica et Biophysica Acta (BBA) - Biomembranes, Vol. 773, Issue 1 https://doi.org/10.1016/0005-2736(84)90561-3	journal	June 1984
The Influence of Short-Chain Alcohols on Interfacial Tension, Mechanical Properties, Area/Molecule, and Permeability of Fluid Lipid Bilayers Ly, Hung V.; Longo, Marjorie L. Biophysical Journal, Vol. 87, Issue 2 https://doi.org/10.1529/biophysj.103.034280	journal	August 2004
Packing properties of 1-alkanols and alkanes in a phospholipid membrane Aagaard, Thomas H.; Kristensen, Mette N.; Westh, Peter Biophysical Chemistry, Vol. 119, Issue 1 https://doi.org/10.1016/j.bpc.2005.09.003	journal	January 2006
How Alcohol Chain-Length and Concentration Modulate Hydrogen Bond Formation in a Lipid Bilayer Dickey, Allison N.; Faller, Roland Biophysical Journal, Vol. 92, Issue 7 https://doi.org/10.1529/biophysj.106.097022	journal	April 2007
Influence of Ethanol on Lipid Membranes: From Lateral Pressure Profiles to Dynamics and Partitioning Terama, Emma; Ollila, O. H. Samuli; Salonen, Emppu The Journal of Physical Chemistry B, Vol. 112, Issue 13 https://doi.org/10.1021/jp0750811	journal	April 2008
Modulation of KvAP Unitary Conductance and Gating by 1-Alkanols and Other Surface Active Agents Finol-Urdaneta, Rocio K.; McArthur, Jeffrey R.; Juranka, Peter F. Biophysical Journal, Vol. 98, Issue 5 https://doi.org/10.1016/j.bpj.2009.10.053	journal	March 2010
The Nanomechanical Properties of Lipid Membranes are Significantly Influenced by the Presence of Ethanol Stetter, Frank W. S.; Hugel, Thorsten Biophysical Journal, Vol. 104, Issue 5 https://doi.org/10.1016/j.bpj.2013.01.021	journal	March 2013
The effect of aliphatic alcohols on fluid bilayers in unilamellar DOPC vesicles — A small-angle neutron scattering and molecular dynamics study Klacsová, M.; Bulacu, M.; Kučerka, N. Biochimica et Biophysica Acta (BBA) - Biomembranes, Vol. 1808, Issue 9 https://doi.org/10.1016/j.bbamem.2011.04.010	journal	September 2011
Lateral Pressures in Cell Membranes: A Mechanism for Modulation of Protein Function Cantor, Robert S. The Journal of Physical Chemistry B, Vol. 101, Issue 10 https://doi.org/10.1021/jp963911x	journal	March 1997
Lipid Bilayer Pressure Profiles and Mechanosensitive Channel Gating Gullingsrud, Justin; Schulten, Klaus Biophysical Journal, Vol. 86, Issue 6 https://doi.org/10.1529/biophysj.103.034322	journal	June 2004
Assessment of Potential Stimuli for Mechano-Dependent Gating of MscL: Effects of Pressure, Tension, and Lipid Headgroups ^† Moe, Paul; Blount, Paul Biochemistry, Vol. 44, Issue 36 https://doi.org/10.1021/bi0509649	journal	September 2005
Protein Shape Change Has a Major Effect on the Gating Energy of a Mechanosensitive Channel Samuli Ollila, O. H.; Louhivuori, Martti; Marrink, Siewert J. Biophysical Journal, Vol. 100, Issue 7 https://doi.org/10.1016/j.bpj.2011.02.027	journal	April 2011
Differential effects of lipids and lyso-lipids on the mechanosensitivity of the mechanosensitive channels MscL and MscS Nomura, T.; Cranfield, C. G.; Deplazes, E. Proceedings of the National Academy of Sciences, Vol. 109, Issue 22 https://doi.org/10.1073/pnas.1200051109	journal	May 2012
Sensing and Responding to Membrane Tension: The Bacterial MscL Channel as a Model System Iscla, Irene; Blount, Paul Biophysical Journal, Vol. 103, Issue 2 https://doi.org/10.1016/j.bpj.2012.06.021	journal	July 2012
The Influence of 1-Alkanols and External Pressure on the Lateral Pressure Profiles of Lipid Bilayers Griepernau, Beate; Böckmann, Rainer A. Biophysical Journal, Vol. 95, Issue 12 https://doi.org/10.1529/biophysj.108.142125	journal	December 2008
Structural Determinants of MscL Gating Studied by Molecular Dynamics Simulations Gullingsrud, Justin; Kosztin, Dorina; Schulten, Klaus Biophysical Journal, Vol. 80, Issue 5 https://doi.org/10.1016/s0006-3495(01)76181-4	journal	May 2001
Chemically Charging the Pore Constriction Opens the Mechanosensitive Channel MscL Yoshimura, Kenjiro; Batiza, Ann; Kung, Ching Biophysical Journal, Vol. 80, Issue 5 https://doi.org/10.1016/s0006-3495(01)76192-9	journal	May 2001
Gating of MscL Studied by Steered Molecular Dynamics Gullingsrud, Justin; Schulten, Klaus Biophysical Journal, Vol. 85, Issue 4 https://doi.org/10.1016/s0006-3495(03)74637-2	journal	October 2003
Mattress model of lipid-protein interactions in membranes Mouritsen, O. G.; Bloom, M. Biophysical Journal, Vol. 46, Issue 2 https://doi.org/10.1016/s0006-3495(84)84007-2	journal	August 1984
Bat coronaviruses related to SARS-CoV-2 and infectious for human cells Temmam, Sarah; Vongphayloth, Khamsing; Baquero, Eduard Nature, Vol. 604, Issue 7905 https://doi.org/10.1038/s41586-022-04532-4	journal	February 2022
Coarse-grained simulation: a high-throughput computational approach to membrane proteins Sansom, Mark S. P.; Scott, Kathryn A.; Bond, Peter J. Biochemical Society Transactions, Vol. 36, Issue 1 https://doi.org/10.1042/bst0360027	journal	January 2008

Cited By (6)

A Practical View of the Martini Force Field Bruininks, Bart M. H.; Souza, Paulo C. T.; Marrink, Siewert J. Methods in Molecular Biology https://doi.org/10.1007/978-1-4939-9608-7_5	book	January 2019
Ceramides bind VDAC2 to trigger mitochondrial apoptosis Dadsena, Shashank; Bockelmann, Svenja; Mina, John G. M. Nature Communications, Vol. 10, Issue 1 https://doi.org/10.1038/s41467-019-09654-4	journal	April 2019
Connecting Structure–Property and Structure–Function Relationships across the Disciplines of Chemistry and Biology: Exploring Student Perceptions Kohn, Kathryn P.; Underwood, Sonia M.; Cooper, Melanie M. CBE—Life Sciences Education, Vol. 17, Issue 2 https://doi.org/10.1187/cbe.18-01-0004	journal	June 2018
Emerging Diversity in Lipid–Protein Interactions Corradi, Valentina; Sejdiu, Besian I.; Mesa-Galloso, Haydee Chemical Reviews, Vol. 119, Issue 9 https://doi.org/10.1021/acs.chemrev.8b00451	journal	January 2019
Unraveling the molecular principles by which ceramides commit cells to death Dadsena, Shashank; Hassan, Dina G.; Holthuis, Joost C. M. Cell Stress, Vol. 3, Issue 8 https://doi.org/10.15698/cst2019.08.196	journal	August 2019
Alcohol Interactions with Lipid Bilayers Kondela, Tomáš; Gallová, Jana; Hauß, Thomas Molecules, Vol. 22, Issue 12 https://doi.org/10.3390/molecules22122078	journal	November 2017

Similar Records

Force transduction and lipid binding in MscL: A continuum-molecular approach

Journal Article · Mon Dec 01 00:00:00 EST 2014 · PLoS ONE · OSTI ID:1346131

Vanegas, Juan M.; Arroyo, Marino; Fotiadis, Dimitrios

Elucidating a role for the cytoplasmic domain in the Mycobacterium tuberculosis mechanosensitive channel of large conductance

Journal Article · Mon Oct 01 00:00:00 EDT 2018 · Scientific Reports · OSTI ID:1346131

Herrera, Nadia; Maksaev, Grigory; Haswell, Elizabeth S.; +1 more

Phylogenetically Driven Sequencing of Extremely Halophilic Archaea Reveals Strategies for Static and Dynamic Osmo-response

Journal Article · Thu Nov 13 00:00:00 EST 2014 · PLoS Genetics · OSTI ID:1346131

Becker, Erin A.; Seitzer, Phillip M.; Tritt, Andrew; +9 more

Related Subjects

59 BASIC BIOLOGICAL SCIENCES

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

Citation Formats

References (64)

Cited By (6)

Similar Records

Related Subjects