Multiscale Modeling of Four Component Lipid Mixtures: Coarse Grained and United Atom Simulations Reveal Trends in Phase Separation

Abstract

The cell plasma membrane is often modeled using three-component mixtures containing a high melting lipid, a low melting lipid and cholesterol. These ternary mixtures exhibit either nanoscopoic or macroscopic liquid-liquid phase coexistence. An additional patterned phase morphology can exist in four component systems which combine a high melting lipid, cholesterol, a nanodomain-inducing low melting lipid and a macrodomain-inducing low melting lipid. The molecular-level details governing these different phase morphologies are not yet known. Here, we utilize molecular dynamics simulations to analyze how phase separation evolves in a four component mixture. We present data for 11 mixtures at a fixed composition of (16:0,16:0)-pc/(18:2,18:2)-pc/(16:0,18:2)-pc/Cholesterol (DPPC/DLiPC/PLiPC/Chol), where PLiPC is incrementally replaced by DLiPC from one simulation to the next. Each simulation was run to equilibrium over 25 μs using the Martini coarse grained forcefield and was then converted to united atom and run for a further 100 ns. We investigate trends in domain size, composition, interleaflet coupling and properties of the domain interface as a function of replacement of PLiPC by DLiPC.