Liposomal delivery systems have been a versatile and successful approach to therapeutics for a variety of diseases. In these systems, it is common to incorporate cholesterol to increase membrane order and reduce membrane permeability. However, the ideal cholesterol:lipid ratio to optimize stable and effective liposome performance is an open question. Here, we study how cholesterol concentrations affect bilayer structure and dynamics, taking into account membranecurvature and asymmetry. Planar and curved bilayer systems were simulated, which correspond to half of a giant liposome and half of a small liposome, respectively. Bilayers were simulated with cholesterol molar ratios of 0%, 10%, 20%, 30%, 40%, and 50%, and biophysical quantities such as area per lipid (APL), thickness, leaflet interdigitation, and deuterium order parameters (SCD) were calculated. We found that for the planar bilayer system, cholesterol has a classical condensing effect by progressively reducing APL from 60 Å 2 to 40 Å 2 , thickening the membrane and ordering the lipids. However, for the curved bilayer system, cholesterol causes an expansion effect where the APL for the inner leaflet increases from 60 Å 2 to 90 Å 2 as cholesterol is increased. Analysis of SCD indicates that cholesterol is ordering the acyl chains up to 40%, beyond which there is no change or a slight decrease due to saturation or frustration in packing. Membrane thickness increased monotonically in the planar system but increased nonlinearly in the curved system due to curvature-induced stress. This study shows that curvature and membrane asymmetry play a large role in how cholesterol affects bilayer properties. While the planar bilayer system can be used to understand the classical effect of cholesterol on a bilayer, the curved system exhibits nonclassical properties that are not well captured by previous models.
Khodadadi et al. (Sun,) studied this question.