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, I) miscible liquid disordered bulk, II) phase separated, domain registered coexistence of liquid disordered and liquid ordered and domains, and III) 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.These collected observations substantially enhance our understanding of the role of Chol in complex phase behavior in ternary lipid mixtures and provide a framework for exploring structure and dynamics of domain formation in future computational, theoretical, and experimental investigations. ASSOCIATED CONTENT Supporting InformationSee supporting information for illustrative demonstrations of order parameters mix , ) , and f , explanation and illustraton of 50% miscibility mapping to mix , and visualizations of f and | f | in all systems. Additionally, order parameters measured for transleaflet clusters and illustrative demonstration of the clustering approach used is supplied.

In-vitroreconstitution of Herpes Simplex Virus 1 fusion identifies low pH as a fusion co-trigger

“…fusion in vitro required cholesterol, with 33% being the optimal concentration. Cholesterol modifies many of the physical properties of membranes, including fluidity, elasticity, thickness, and domain formation (71,73,77,82,(102)(103)(104)(105)(106)(107)(108)(109), reviewed in (75), in a concentration-dependent manner (71)(72)(73)(74). Many enveloped viruses require cholesterol either in the host cell membrane or the viral envelope for entry (40,41,(63)(64)(65)(66)(67)(68)(69)(70).…”