How cholesterol stiffens unsaturated lipid membranes

Cholesterol is an integral component of eukaryotic cell membranes and a key molecule in controlling membrane fluidity, organization, and other physicochemical parameters. It also plays a regulatory function in antibiotic drug resistance and the immune response of cells against viruses, by stabilizin...

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Published in:Proceedings of the National Academy of Sciences - PNAS Vol. 117; no. 36; p. 21896
Main Authors: Chakraborty, Saptarshi, Doktorova, Milka, Molugu, Trivikram R, Heberle, Frederick A, Scott, Haden L, Dzikovski, Boris, Nagao, Michihiro, Stingaciu, Laura-Roxana, Standaert, Robert F, Barrera, Francisco N, Katsaras, John, Khelashvili, George, Brown, Michael F, Ashkar, Rana
Format: Journal Article
Language:English
Published: United States 08.09.2020
Subjects:
Biomechanical Phenomena
Cell Membrane - chemistry
Cell Membrane - metabolism
Cholesterol - chemistry
Cholesterol - metabolism
Magnetic Resonance Spectroscopy
Membrane Fluidity
Membrane Lipids - chemistry
Membrane Lipids - metabolism
Molecular Dynamics Simulation
molecular dynamics simulations
membrane viscosity
deuterium NMR
area compressibility
neutron spin echo
ISSN:1091-6490, 1091-6490
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Summary:Cholesterol is an integral component of eukaryotic cell membranes and a key molecule in controlling membrane fluidity, organization, and other physicochemical parameters. It also plays a regulatory function in antibiotic drug resistance and the immune response of cells against viruses, by stabilizing the membrane against structural damage. While it is well understood that, structurally, cholesterol exhibits a densification effect on fluid lipid membranes, its effects on membrane bending rigidity are assumed to be nonuniversal; i.e., cholesterol stiffens saturated lipid membranes, but has no stiffening effect on membranes populated by unsaturated lipids, such as 1,2-dioleoyl- -glycero-3-phosphocholine (DOPC). This observation presents a clear challenge to structure-property relationships and to our understanding of cholesterol-mediated biological functions. Here, using a comprehensive approach-combining neutron spin-echo (NSE) spectroscopy, solid-state deuterium NMR ( H NMR) spectroscopy, and molecular dynamics (MD) simulations-we report that cholesterol locally increases the bending rigidity of DOPC membranes, similar to saturated membranes, by increasing the bilayer's packing density. All three techniques, inherently sensitive to mesoscale bending fluctuations, show up to a threefold increase in effective bending rigidity with increasing cholesterol content approaching a mole fraction of 50%. Our observations are in good agreement with the known effects of cholesterol on the area-compressibility modulus and membrane structure, reaffirming membrane structure-property relationships. The current findings point to a scale-dependent manifestation of membrane properties, highlighting the need to reassess cholesterol's role in controlling membrane bending rigidity over mesoscopic length and time scales of important biological functions, such as viral budding and lipid-protein interactions.
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ISSN:1091-6490
1091-6490
DOI:10.1073/pnas.2004807117