Regimes of Complex Lipid Bilayer Phases Induced by Cholesterol Concentration in MD Simulation

Abstract

Cholesterol is essential to the formation of phase-separated lipid domains in membranes. Lipid domains can exist in different thermodynamic phases depending on the molecular composition and play significant roles in determining structure and function of membrane proteins. We investigate the role of cholesterol in the structure and dynamics of ternary lipid mixtures displaying phase separation using molecular dynamics simulations, employing a physiologically relevant span of cholesterol concentration. We find that cholesterol can induce formation of three regimes of phase behavior: 1) miscible liquid-disordered bulk, 2) phase-separated, domain-registered coexistence of liquid-disordered and liquid-ordered domains, and 3) phase-separated, domain-antiregistered coexistence of liquid-disordered and newly identified nanoscopic gel domains composed of cholesterol threads we name “cholesterolic gel” domains. These findings are validated and discussed in the context of current experimental knowledge, models of cholesterol spatial distributions, and models of ternary lipid-mixture phase separation.