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 iswell 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-snglycero-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 (2H 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-compressibilitymodulus andmembrane 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.
| Original language | English |
|---|---|
| Pages (from-to) | 21896-21905 |
| Number of pages | 10 |
| Journal | Proceedings of the National Academy of Sciences of the United States of America |
| Volume | 117 |
| Issue number | 36 |
| DOIs | |
| State | Published - Sep 8 2020 |
Funding
We thank E. G. Kelley for discussions and assistance in SANS and NSE data collection. We also acknowledge the use of neutron-scattering facilities at NIST and ORNL. R.A. was supported by faculty startup funds from the state of Virginia and the Clifford G. Shull Fellowship program sponsored by the Neutron Sciences Directorate at ORNL. F.N.B. received partial support from NIH Grant R01GM120642, and F.A.H. was supported by NSF Grant MCB-1817929. G.K. was supported by the 1923 Fund. J.K. is supported through the Scientific User Facilities Division of the Department of Energy (DOE) Office of Science, sponsored by the Basic Energy Science (BES) Program, DOE Office of Science, under Contract DEAC05-00OR22725. M.N. was supported by Cooperative Agreement 70NANB15H259 from NIST, U.S. Department of Commerce. M.F.B. was supported by NIH Grant R01EY026041 and NSF Grants MCB-1817862 and CHE-1904125. M.D. was supported by NIH Grant 1F32GM134704-01. Access to the NIST SANS and NSE beamlines was provided by the Center for High Resolution Neutron Scattering, a partnership between the NIST and the NSF under Agreement DMR-1508249. Research conducted at ORNL's SNS was sponsored by the Scientific User Facilities Division, Office of BES, US DOE. ORNL is managed by UT-Battelle, LLC under US DOE Contract DE-AC05-00OR22725. ACERT is supported by NIH Grants P41GM103521 and R01GM123779. This work benefited from the use of the SasView application, originally developed under NSF Award DMR-0520547. Any mention of commercial products within NIST web pages is for information only; it does not imply recommendation or endorsement by NIST.
Keywords
- Area compressibility
- Deuterium NMR
- Membrane viscosity
- Molecular dynamics simulations
- Neutron spin echo