Complexes in ternary cholesterol-phospholipid mixtures

Abstract

Recent work by Veatch and Keller has described micron-scale liquid-liquid immiscibility in giant unilamellar vesicles composed of ternary mixtures of cholesterol, dipalmitoylphosphatidylcholine (DPPC), and dioleoylphosphatidylcholine (DOPC). Significantly, they do not observe micron-scale immiscibility in any of the three corresponding binary mixtures under the same conditions. It is shown here that this unexpected result can be accounted for by the formation of a complex between cholesterol and DPPC. The complex is miscible with DPPC and cholesterol, and immiscible with DOPC. A simple, idealized thermodynamic treatment of this model leads to theoretical ternary phase diagrams that are similar to the experimental diagram reported by Veatch and Keller. The model also accounts for significant qualitative features of the deuterium NMR spectra of these mixtures in bilayers.

FIGURE 1

Calculated phase diagram for a ternary mixture of cholesterol, a reactive phospholipid (DPPC), and an unreactive phospholipid (DOPC). The reaction is assumed to go to completion. The large dots give locations of the two critical points, and the straight lines illustrate tie-lines.

FIGURE 2

Calculated relative order parameter S for the reactive phospholipid molecules as a function of temperature (K). The critical temperature and composition are ∼311.8° and 0.372 mol fraction for both cholesterol and reactive phospholipid. Below the critical point, two phases are present with the different order parameters.