Multiscale modeling of four-component lipid mixtures: domain composition, size, alignment, and properties of the phase interface.

Simplified lipid mixtures are often used to model the complex behavior of the cell plasma membrane. Indeed, as few as four components-a high-melting lipid, a nandomain-inducing low-melting lipid, a macrodomain-inducing low-melting lipid, and cholesterol (chol)-can give rise to a wide range of domain sizes and patterns that are highly sensitive to lipid compositions. Although these systems are studied extensively with experiments, the molecular-level details governing their phase behavior are not yet known. We address this issue by using molecular dynamics simulations to analyze how phase separation evolves in a four-component system as it transitions from small domains to large domains. To do so, we fix concentrations of the high-melting lipid 16:0,16:0-phosphatidylcholine (DPPC) and chol, and incrementally replace the nanodomain-inducing low-melting lipid 16:0,18:2-PC (PUPC) by the macrodomain-inducing low-melting lipid 18:2,18:2-PC (DUPC). Coarse-grained simulations of this four-component system reveal that lipid demixing increases as the amount of DUPC increases. Additionally, we find that domain size and interleaflet alignment change sharply over a narrow range of replacement of PUPC by DUPC, indicating that intraleaflet and interleaflet behaviors are coupled. Corresponding united atom simulations show that only lipids within ∼2 nm of the phase interface are significantly perturbed regardless of domain composition or size. Thus, whereas the fraction of interface-perturbed lipids is negligible for large domains, it is significant for smaller ones. Together, these results reveal characteristic traits of bilayer thermodynamic behavior in four-component mixtures, and provide a baseline for investigation of the effects of proteins and other lipids on membrane phase properties.