Distribution of Cholesterol in Asymmetric Membranes Driven by Composition and Differential Stress

Abstract

Many biological membranes, in particular plasma membranes of eukaryotic cells, are asymmetric, which means that their two leaflets differ from one another. This asymmetry can arise in a number of ways, and we focus on the following two: a difference in lipid type, and a difference in lateral stress, arising from overfilling one leaflet with respect to the other. The two ways presuppose that lipids, once put in a given leaflet, stay in that leaflet. This is true for most phospholipids, but not for cholesterol, which transitions rapidly enough between leaflets so that its distribution is determined by chemical equilibrium. Given that compressive stress presumably excludes cholesterol from a leaflet, while preferential partitioning can draw it into a leaflet, this poses the question of how these two types of asymmetry cooperatively affect the distribution of cholesterol. Using a highly coarse-grained membrane model, we investigate how these two driving forces play against each other until cholesterol's chemical potential is equilibrated. We also model this system theoretically using two coupled elastic sheets whose composition degrees of freedom are described by a simple lattice gas model with a non-ideal mixing parameter χ. We find that the results from the simulations agree with the predictions if we allow for just one free parameter, which empirically determines how χ relates to the non-ideal interaction energy between cholesterol and lipids in either of the two leaflets. We anticipate that our simple model can help shed light on the longstanding puzzle of how cholesterol distributes in cellular plasma membranes, and whether the resulting equilibrium puts them under differential stress.