Cholesterol and ether lipids are ubiquitous in mammalian cell membranes, and their interactions are crucial in delineating ether lipid mediated cholesterol trafficking. Here we report cholesterol's molecular interactions with ether lipids using a combination of small-angle neutron and x-ray scattering, and molecular dynamics simulations. Specifically, we found that in ether membranes, cholesterol primarily hydrogen bonds with the headgroup's phosphate oxygen, while in the ester counterparts cholesterol predominantly hydrogen bonds with the backbone ester carbonyl. This unique mode of interactions between ether lipids and cholesterol causes cholesterol to migrate closer to the bilayer surface, eliciting dehydration near the headgroup's phosphate moiety. In addition, lipid chain spatial density distributions around a cholesterol molecule indicate isotropic chain packing, a primary cause for cholesterol ring tilt. The insights gained into cholesterol's interactions with ether lipid molecules lend a general understanding to the molecular mechanism of ether lipid mediated cholesterol trafficking.

Backbone moiety of phospholipids determines cholesterol disposition

245th National Meeting (2013)

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