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Title: How cholesterol stiffens unsaturated lipid membranes

Abstract

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- sn -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 ( 2 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 themore » 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.« less

Authors:
; ORCiD logo; ORCiD logo; ORCiD logo; ; ; ORCiD logo; ; ; ORCiD logo; ORCiD logo; ORCiD logo; ORCiD logo; ORCiD logo
Publication Date:
Research Org.:
Oak Ridge National Laboratory (ORNL), Oak Ridge, TN (United States)
Sponsoring Org.:
USDOE Office of Science (SC), Basic Energy Sciences (BES)
OSTI Identifier:
1650412
Alternate Identifier(s):
OSTI ID: 1684661
Grant/Contract Number:  
AC05-00OR22725
Resource Type:
Published Article
Journal Name:
Proceedings of the National Academy of Sciences of the United States of America
Additional Journal Information:
Journal Name: Proceedings of the National Academy of Sciences of the United States of America Journal Volume: 117 Journal Issue: 36; Journal ID: ISSN 0027-8424
Publisher:
National Academy of Sciences
Country of Publication:
United States
Language:
English
Subject:
59 BASIC BIOLOGICAL SCIENCES; area compressibility; membrane viscosity; deuterium NMR; neutron spin echo; molucular dynamics simulations

Citation Formats

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., and Ashkar, Rana. How cholesterol stiffens unsaturated lipid membranes. United States: N. p., 2020. Web. doi:10.1073/pnas.2004807117.
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. How cholesterol stiffens unsaturated lipid membranes. United States. https://doi.org/10.1073/pnas.2004807117
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., and Ashkar, Rana. Tue . "How cholesterol stiffens unsaturated lipid membranes". United States. https://doi.org/10.1073/pnas.2004807117.
@article{osti_1650412,
title = {How cholesterol stiffens unsaturated lipid membranes},
author = {Chakraborty, Saptarshi and Doktorova, Milka and Molugu, Trivikram R. and Heberle, Frederick A. and Scott, Haden L. and Dzikovski, Boris and Nagao, Michihiro and Stingaciu, Laura-Roxana and Standaert, Robert F. and Barrera, Francisco N. and Katsaras, John and Khelashvili, George and Brown, Michael F. and Ashkar, Rana},
abstractNote = {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- sn -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 ( 2 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.},
doi = {10.1073/pnas.2004807117},
journal = {Proceedings of the National Academy of Sciences of the United States of America},
number = 36,
volume = 117,
place = {United States},
year = {Tue Aug 25 00:00:00 EDT 2020},
month = {Tue Aug 25 00:00:00 EDT 2020}
}

Journal Article:
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https://doi.org/10.1073/pnas.2004807117

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