Cholesterol-induced domain formation in multi-component lipid membranes

Abstract

A cholesterol oxidase (COD) enzyme reaction assay has been developed to measure the chemical potential of cholesterol in various PC/cholesterol bilayers, and the result was compared with the predictions from four major lipid-cholesterol interaction models. In PC bilayers with chains containing single cis double bonds, the chemical potential of cholesterol displays vertical jumps, indicating large-scale superlattice formation, at cholesterol mole fractions of 0.15, 0.25, 0.40, .50 and 0.57, and peaks at the cholesterol maximum solubility limit in the bilayers. No such jump below = 0.50 was observed in PC bilayers with all saturated chains or with chains containing 3 cis double bonds. PC with trans double bond showed similar mixing behavior to PC with cis double bond. The result provided solid supportive evidences for the cholesterol chemical potential predicted from the Monte Carlo simulations based on the Umbrella model. Interestingly, the cholesterol maximum solubility shifted to lower when cholesterol was substituted by ceramide, a molecule having similar small headgroup like cholesterol. The result supported an earlier speculation of the Umbrella model.

In another study, we have used lattice model Monte Carlo simulations to reproduce experimental phase boundaries of DOPC/DSPC/Cholesterol obtained by Feigenson group in Cornell University through multiple experimental techniques. A new computational technique, named the "Composition Evaluation Method", which is about 10 ~ 30 times more efficient in determining phase boundaries comparing to the traditional free energy calculation, has been implemented to determine the compositions of the coexisting phases. We found that pairwise interactions can reproduce the experimental critical point as well as the slope of tie lines, but not the compositions of the coexisting phases.