Thermodynamics of Lipid Organization and Domain Formation in Phospholipid Bilayers

Abstract

Lipid organization and domain formation in phospholipid membranes has a large impact on a number of physical membrane properties such as membrane elasticity, lipid lateral diffusion, permeability, and binding properties for peptides and proteins. The mixing behavior of lipids can be deduced from the binary phase diagram, i.e. temperature versus mole fraction diagram, describing the temperature induced phase transition behavior of lipid mixtures. An easy way to obtain experimental data to construct a binary phase diagram is differential scanning calorimetry (DSC) of aqueous dispersions of liposomes of lipid mixtures. The temperatures that correspond to points on the liquidus and solidus curves of the phase diagram are determined from the DSC thermograms, e.g. the experimental heat capacity curves. The main problem to solve is the correct determination of the onset and end of the melting curve for every single transition curve in a standardized manner, because of the lack of theoretically justified methods. To avoid this subjective procedure, we have developed a method for the simulation of heat capacity curves that are obtained by DSC. Our model uses a thermodynamic approach for the description of the miscibility of phospholipids, which is based on regular solution theory with an incorporation of a broadening function, taking into account the reduced cooperativity in mixed lipid bilayer systems. The output parameters of these simulations are nonideality parameters describing nonideal mixing in the gel and liquid crystalline phase, the temperature set describing the onset and end of melting, respectively, and a value for the cooperative unit size. These temperature data are then used for the construction and simulation of the phase diagrams. A four parameter model was used, taking into account the asymmetry of the mixing behavior, yielding two nonideality parameters for each phase. These nonideality parameters describe the interaction of both components in the single phase regions. We have employed this procedure to describe the mixing behavior of various binary phospholipid systems. We will show how the mixing behavior is influenced by changing the hydrocarbon chain length of one of the component, by changing the lipid-lipid head group interaction, or the pH and ionic strength of the dispersion. Examples of binary lipid mixtures in which domain formation in the liquid crystalline phase is observed, are presented.