Interactions between Ether Phospholipids and Cholesterol As Determined by Scattering and Molecular Dynamics Simulations

Abstract

Cholesterol and ether lipids are ubiquitous in mammalian cell membranes, and their interactions are crucial in ether lipid mediated cholesterol trafficking. We report on cholesterol’s molecular interactions with ether lipids as determined using a combination of small-angle neutron and X-ray scattering, and all-atom molecular dynamics (MD) simulations. A scattering density profile model for an ether lipid bilayer was developed using MD simulations, which was then used to simultaneously fit the different experimental scattering data. From the analysis of the data the various bilayer structural parameters were obtained. Surface area constrained MD simulations were also performed to reproduce the experimental data. This iterative analysis approach resulted in good agreement between the experimental and simulated form factors. The molecular interactions taking place between cholesterol and ether lipids were then determined from the validated MD simulations. We found that in ether membranes, cholesterol primarily hydrogen bonds with the lipid headgroup phosphate oxygen, while in their ester membrane counterparts, cholesterol hydrogen bonds with the backbone ester carbonyls. This different mode of interaction between ether lipids and cholesterol induces cholesterol to reside closer to the bilayer surface, dehydrating the headgroup’s phosphate moiety. Moreover, the three-dimensional lipid chain spatial density distribution around cholesterol indicates anisotropic chain packing, causing cholesterol to tilt. These insights lend a better understanding of ether lipid mediated cholesterol trafficking and the roles that the different lipid species have in determining the structural and dynamical properties of membrane associated biomolecules.

Thickness Mismatch of Coexisting Liquid Phases in Noncanonical Lipid Bilayers

“…13, 41–44 Second, the Lo phase contains higher fractions of saturated lipids, and cholesterol has been reported to preferentially thicken the hydrophobic regions of single-component membranes comprised of saturated lipids more than it thickens those comprised of unsaturated lipids. 17, 48 Cholesterol likely increases the thickness of the lipid headgroup regions within membranes as well, 49 perhaps differentially. However, the reasoning above is not necessarily general.…”

On the road to unraveling the molecular functions of ether lipids

“…The effect of cholesterol on membranes composed of ether lipids versus ester bond lipids is even more difficult to interpret even though it has been the subject of several publications . Hianik et al .…”

Lateral organization, bilayer asymmetry, and inter-leaflet coupling of biological membranes

“…More recently, AAMD simulations were used to determine the biomembrane bending modulus (K c ) based on the analysis of thermal fluctuations in lipid orientations, where the effects of lipid tilting decouple from the lipid orientation energetics associated with bending moduli 145 . AAMD simulation has also been combined with X-ray and neutron scattering techniques to study the structure and dynamics of pure lipid bilayers and the effects of lipid modifications 146,147 or the addition of various small organic molecules, such as cholesterol 146 , carotenoids 148 , and tamoxifen 149 .…”