A Simple Thermodynamic Model of the Liquid-Ordered State and the Interactions between Phospholipids and Cholesterol

A theoretical model is proposed to describe the heat capacity function and the phase behavior of binary mixtures of phospholipids and cholesterol. The central idea is that the liquid-ordered state (Lo) is a thermodynamic state or an ensemble of conformations of the phospholipid, characterized by enthalpy and entropy functions that are intermediate between those of the solid and the liquid-disordered (Ld) states. The values of those thermodynamic functions are such that the Lo state is not appreciably populated in the pure phospholipid, at any temperature, because either the solid or the Ld state have much lower free energies. Cholesterol stabilizes the Lo state by nearest-neighbor interactions, giving rise to the appearance of the Lo phase. The model is studied by Monte Carlo simulations on a lattice with nearest-neighbor interactions, which are derived from experiment as much as possible. The calculated heat capacity function closely resembles that obtained by calorimetry. The phase behavior produced by the model is also in agreement with experimental data. The simulations indicate that separation between solid and Lo phases occurs below the melting temperature of the phospholipid (Tm). Above Tm, small Ld and Lo domains do exist, but there is no phase separation.