title: 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 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.
authors.affiliation: Neutron Sciences Directorate, Oak Ridge National Laboratory, Oak Ridge, Tennessee 37831, United States. panj@ornl.gov
authors.forename: Jianjun
authors.initials: J
authors.lastname: Pan
authors.forename: Xiaolin
authors.initials: X
authors.lastname: Cheng
authors.forename: Frederick A
authors.initials: FA
authors.lastname: Heberle
authors.forename: Barmak
authors.initials: B
authors.lastname: Mostofian
authors.forename: Norbert
authors.initials: N
authors.lastname: Kučerka
authors.forename: Paul
authors.initials: P
authors.lastname: Drazba
authors.forename: John
authors.initials: J
authors.lastname: Katsaras
mesh_terms: D002784:Cholesterol / Q000737:chemistry*; D008051:Lipid Bilayers / Q000737:chemistry; D056004:Molecular Dynamics Simulation; D033363:Neutron Diffraction; D010742:Phospholipid Ethers / Q000737:chemistry*; D053838:Scattering, Small Angle; D014961:X-Ray Diffraction
chemical_list: C052298:1,2-dihexadecyl-sn-glycero-3-phosphocholine; D008051:Lipid Bilayers; D010742:Phospholipid Ethers; D002784:Cholesterol