Reply to Nagle et al.: The universal stiffening effects of cholesterol on lipid membranes

Ashkar, Rana; Doktorova, Milka; Heberle, Frederick A.; Scott, Haden L.; Barrera, Francisco N.; Katsaras, John; Khelashvili, George; Brown, Michael F.

doi:10.1073/pnas.2102845118

Cited by 18 publications

(28 citation statements)

References 11 publications

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“…These three techniques separately indicated the increase of bending rigidity with the increase of cholesterol content in the membranes of DOPC vesicles. After publishing a recent work [44], the above finding has been a controversial topic [45,46]. Later, a paper has been proposed to reconcile this controversy [47].…”

Section: Plos Onementioning

confidence: 99%

Effects of cholesterol on the size distribution and bending modulus of lipid vesicles

et al. 2022

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The influence of cholesterol fraction in the membranes of giant unilamellar vesicles (GUVs) on their size distributions and bending moduli has been investigated. The membranes of GUVs were synthesized by a mixture of two elements: electrically neutral lipid 1, 2-dioleoyl-sn-glycero-3-phosphocholine (DOPC) and cholesterol and also a mixture of three elements: electrically charged lipid 1,2-dioleoyl-sn-glycero-3-phospho-(1′-rac-glycerol) (DOPG), DOPC and cholesterol. The size distributions of GUVs have been presented by a set of histograms. The classical lognormal distribution is well fitted to the histograms, from where the average size of vesicle is obtained. The increase of cholesterol content in the membranes of GUVs increases the average size of vesicles in the population. Using the framework of Helmholtz free energy of the system, the theory developed by us is extended to explain the experimental results. The theory determines the influence of cholesterol on the bending modulus of membranes from the fitting of the proper histograms. The increase of cholesterol in GUVs increases both the average size of vesicles in population and the bending modulus of membranes.

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Section: Plos Onementioning

confidence: 99%

Effects of cholesterol on the size distribution and bending modulus of lipid vesicles

et al. 2022

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“…The atomic resolution of the simulations allowed us to further identify the region in the bilayer where the square-law dependence holds, revealing the importance of interleaflet interactions for the collective dynamics of the lipids. The apparent bilayer bending moduli emerging from the application of an NMR-based formalism to the simulation data are corroborated by results from an alternative computational method, as well as NMR and neutron spin echo (NSE) experiments (85,86). Our MD simulations thus successfully replicate NMR observables and validate their interpretation while offering new insights about their physical origins.…”

Section: Discussionmentioning

confidence: 68%

“…That the lipid composition of a membrane affects its structure and function is a universally acknowledged fact (9,10,(83)(84)(85)(86). However, considerably less is known about the level of cooperativity of the fluctuations of individual lipid molecules that give rise to the emerging bilayer properties.…”

Section: Discussionmentioning

confidence: 99%

“…Both approaches at the global and more local scales, have been shown to yield similar results for some bilayers (e.g., saturated lipids with and without cholesterol), but contradictory results for other types of bilayers (e.g., di-unsaturated lipids with cholesterol (86)). The sources of these discrepancies may lie in the time- and length-scales of the underlying dynamics (85,86) and are the subject of ongoing research.…”

Section: Discussionmentioning

confidence: 99%

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Molecular Simulations and NMR Reveal How Lipid Fluctuations Affect Membrane Mechanics

Doktorova

Khelashvili

Ashkar

et al. 2022

Preprint

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Lipid bilayers form the main matrix of functional cell membranes, and their dynamics underlie a host of physical and biological processes. Here we show that elastic membrane properties and collective molecular dynamics are related by the mean-square amplitudes (order parameters) and relaxation rates (correlation times) of lipid acyl chain motions. We performed all-atom molecular dynamics simulations of liquid-crystalline bilayers to further interpret available NMR data. Our analysis entailed development of a theoretical framework that allows direct comparison of carbon-hydrogen (CH) bond relaxations as measured by simulations and NMR experiments. The new formalism enables validation of lipid force fields against NMR data by including a fixed bilayer normal (director axis) and restricted anisotropic motion of the CH bonds described by their segmental order parameters. The simulated spectral density of thermally excited CH bond fluctuations exhibited well-defined spin-lattice (Zeeman) relaxations analogous to those measured by solid-state NMR spectroscopy. Their frequency signature could be fit to a simple power-law function, indicative of collective dynamics of a nematic-like nature. The calculated spin-lattice relaxation rates scaled as the squared order parameters of the lipid acyl chains yielding an apparent bending modulus κc of the bilayer. Our results show a strong correlation with κc values obtained from solid-state NMR studies of 1,2-dimyristoyl-sn-glycero-3-phosphocholine (DMPC) bilayers with varying amounts of cholesterol as further validated by neutron spin-echo measurements of membrane elasticity. The simulations uncover a critical role of interleaflet coupling in membrane mechanics and thus provide insights into the molecular sites of emerging elastic properties within lipid bilayers.

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“…To explain this effect of cholesterol, we note that for a long time cholesterol has been known to stiffen saturated lipid membranes, and recently, Chakraborty et al have shown that cholesterol also increases the bending rigidity of unsaturated lipid membranes. 62–64 This suggests that cholesterol should also stiffen membranes that are made up of a mixture of saturated and unsaturated lipids, which is the case for our membrane models. In this context, the reduction in cholesterol is one of the factors that causes the softening of cancer cell membranes.…”

Section: Resultsmentioning

confidence: 80%

Elastic moduli of normal and cancer cell membranes revealed by molecular dynamics simulations

Nguyen

Man

et al. 2022

Phys. Chem. Chem. Phys.

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Reply to Nagle et al.: The universal stiffening effects of cholesterol on lipid membranes

Cited by 18 publications

References 11 publications

Effects of cholesterol on the size distribution and bending modulus of lipid vesicles

Effects of cholesterol on the size distribution and bending modulus of lipid vesicles

Molecular Simulations and NMR Reveal How Lipid Fluctuations Affect Membrane Mechanics

Elastic moduli of normal and cancer cell membranes revealed by molecular dynamics simulations

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