The effect of cholesterol on short- and long-chain monounsaturated lipid bilayers as determined by molecular dynamics simulations and X-ray scattering

Norbert Kučerka, Jason D. Perlmutter, Jianjun Pan, Stephanie Tristram-Nagle, John Katsaras, Jonathan N. Sachs

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We investigate the structure of cholesterol-containing membranes composed of either short-chain (diC14:1PC) or long-chain (diC22:1PC) monounsaturated phospholipids. Bilayer structural information is derived from all-atom molecular dynamics simulations, which are validated via direct comparison to x-ray scattering experiments. We show that the addition of 40 mol % cholesterol results in a nearly identical increase in the thickness of the two different bilayers. In both cases, the chain ordering dominates over the hydrophobic matching between the length of the cholesterol molecule and the hydrocarbon thickness of the bilayer, which one would expect to cause a thinning of the diC22:1PC bilayer. For both bilayers there is substantial headgroup rearrangement for lipids directly in contact with cholesterol, supporting the so-called umbrella model. Importantly, in diC14:1PC bilayers, a dynamic network of hydrogen bonds stabilizes long-lived reorientations of some cholesterol molecules, during which they are found to lie perpendicular to the bilayer normal, deep within the bilayer's hydrophobic core. Additionally, the simulations show that the diC14:1PC bilayer is significantly more permeable to water. These differences may be correlated with faster cholesterol flip-flop between the leaflets of short-chain lipid bilayers, resulting in an asymmetric distribution of cholesterol molecules. This asymmetry was observed experimentally in a case of unilamellar vesicles (ULVs), and reproduced through a set of novel asymmetric simulations. In contrast to ULVs, experimental data for oriented multilamellar stacks does not show the asymmetry, suggesting that it results from the curvature of the ULV bilayers.

Original languageEnglish (US)
Pages (from-to)2792-2805
Number of pages14
JournalBiophysical journal
Issue number6
StatePublished - Sep 15 2008

Bibliographical note

Funding Information:
Access to instruments at the Cornell High Energy Synchrotron Source (CHESS) was funded by a National Science Foundation grant DMR-0225180. N.K was supported through the Visiting Fellow program of the Natural Sciences and Engineering Research Council of Canada. Computational resources were provided by the Minnesota Supercomputer Institute, as well as by Yale University, with the support of Nicholas Carriero and Robert Bjornson. S.T.N. and J.P. were supported by the General Medicine Institute of the National Institutes of Health (GM 44976).


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