Ternary Lipid Domain Formation using Atomistic Molecular Dynamics Simulations

Abstract

Lipid rafts are membrane bilayer micro-domains that are thought to compartmentalize cell processes, though their existence has not yet been demonstrated. Understanding phase separation of model membranes containing cholesterol is a crucial step to understanding the properties of lipid rafts. We study the role of cholesterol and lipid tail unsaturation in phase separation behaviour of phosphatidylcholine lipids using atomistic molecular dynamics simulations. We ran a 10-microsecond simulation of a large randomized bilayer of distearoyl-phosphatidylcholine (DSPC), dilinoleoyl-phosphatidylcholine (DLPC), and cholesterol and directly observe domain formation (liquid ordered and liquid disordered coexistence). Phase-separated stripe domains were simulated to determine the free energy for the exchange of a single DSPC and DLPC between the liquid-ordered and liquid-disordered domains. We performed free energy decompositions and also further partition the enthalpic contributions, which we plot over the surface of the bilayer. Interestingly, we found that it is enthalpically favourable for a single lipid of either type (DSPC or DLPC) to be present in the liquid-ordered phase and also that there seems to exist a correlation between lipid tail enthalpy, lipid tail-order parameter, and local occupancy, suggesting certain roles for cholesterol. We determine atomistic-resolution driving forces for domain formation in ternary lipid mixtures.