A statistical mechanical model of cholesterol/phospholipid mixtures: Linking condensed complexes, superlattices, and the phase diagram

Despite extensive studies for nearly three decades, lateral distribution of molecules in cholesterol/phospholipid bilayers remains elusive. Here we present a statistical mechanical model of cholesterol/phospholipid mixtures that is able to rationalize almost every critical mole fraction (X _cr) value previously reported for sterol superlattice formation as well as the observed biphasic changes in membrane properties at X _cr. This model is able to explain how cholesterol superlattices and cholesterol/phospholipid condensed complexes are interrelated. It gives a more detailed characterization of the LG _Iregion (a broader region than the liquid disordered-liquid ordered mixed-phase region), which is considered to be a sludgelike mixture of fluid phase and aggregates of rigid clusters. A rigid cluster is formed by a cholesterol molecule and phospholipid molecules that are condensed to the cholesterol. Rigid clusters of similar size tend to form aggregates, in which cholesterol molecules are regularly distributed into superlattices. According to this model, the extent and type of sterol superlattices, thus the lateral distribution of the entire membrane, should vary with cholesterol mole fraction in a delicate, predictable, and nonmonotonic manner, which should have profound functional implications.