High-Throughput Simulations Reveal Membrane-Mediated Effects of Alcohols on MscL Gating
| Autor: | Neeraj Kumar, Helgi I. Ingólfsson, Martin Walko, Hendrik R Sikkema, Clement Arnarez, Armagan Kocer, Siewert J. Marrink, Manuel N. Melo, Herman J. C. Berendsen |
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| Přispěvatelé: | Molecular Dynamics, Enzymology, Groothuis lab, Molecular Neuroscience and Ageing Research (MOLAR) |
| Rok vydání: | 2017 |
| Předmět: |
0301 basic medicine
Octanol Octanols MOLECULAR-DYNAMICS SIMULATIONS MECHANOSENSITIVE ION-CHANNEL SHORT-CHAIN ALCOHOLS Gating Molecular Dynamics Simulation 01 natural sciences Biochemistry Ion Channels Article Catalysis LIPID-BILAYER 03 medical and health sciences chemistry.chemical_compound Colloid and Surface Chemistry Mechanosensitive ion channel Bacterial Proteins COARSE-GRAINED MODEL 0103 physical sciences Lipid bilayer Ion channel Mechanical Phenomena PROTEIN FUNCTION Ethanol 010304 chemical physics Chemistry Bilayer Cell Membrane fungi General Chemistry Crystallography 030104 developmental biology Membrane ESCHERICHIA-COLI FORCE-FIELD Biophysics LATERAL PRESSURE PROFILES Mechanosensitive channels MYCOBACTERIUM-TUBERCULOSIS Ion Channel Gating |
| Zdroj: | Journal of the American Chemical Society, 139(7), 2664-2671. AMER CHEMICAL SOC Journal of the American Chemical Society |
| ISSN: | 1520-5126 0002-7863 |
| DOI: | 10.1021/jacs.6b11091 |
| Popis: | 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. 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. |
| Databáze: | OpenAIRE |
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