Mixing behavior of saturated- and unsaturated-tail lipids in the presence and absence of cholesterol.
Participating Group members : Makoto Mori, Patrick Coppock

Coexistence between ordered and disordered fluid domains may be a ubiquitous phenomenon within mammalian cells where cholesterol is a major component, according to a number of lines of evidence. Ternary bilayers comprised of two lipids with different degrees of fluidity (typically, one with saturated tails and the other with cis-monounsaturated tails) along with cholesterol have been proposed as model systems for this phenomenon. A full phase diagram has been generated for DPPC/DOPC/cholesterol sytems that includes a region of coexistence between liquid-ordered (cholesterol and DPPC-rich) and liquid-disordered (DOPC-rich) domains, with tie-lines connecting the coexisting compositions. Many molecular simulation studies have looked at the structure of cholesterol-containing bilayers and confirmed that these have the hallmarks of the liquid-ordered phase. With few exceptions, atomistic simulations have not addressed the free energies of mixing and demixing that drive the phase separation, or even confirmed that the simulation models exhibit the tendency towards phase separation known from experiment. Using the MC/MD approach we were able to confirm that the commonly used Berger forcefield displays the tendency towards phase separation, but that the difference in affinity of DPPC and DOPC for cholesterol-rich environments is weaker than in experiment. Furthermore, simulations indicated that the tendency relies on cooperative effects of interactions between the bilayer components, and cannot be described by simple nearest-neighbor lattice models. Part of this cooperativity, it was shown, is due the dependence of cholesterol-lipid interactions on the degree of cholesterol alignment with the bilayer. (de Joannis et al., J. Am. Chem. Soc. 2011)

Work in progress aims to explain why some small alterations to the structure of cholesterol, namely addition of a methyl ester group beta to the existing hydroxyl, eliminates the tendency to phase separate. In contrast to alterations involving hydroxylation of the hydrophobic tail, which dramatically change the alignment of the molecule within the bilayer, the structural effects of beta-esterification are much more subtle. A related effort is the study of curcumin behavior in the bilayer. Curcumin is a natural component of turmeric that has displayed a range of bioactivity, and whose analogs are under investigation for potential anti-cancer activity. It has a high affinity for lipids, and there have been reports of dramatic effects on bilayer structure at low concentrations, prompting discussions that its bioactivity could result from cholesterol-like influences on bilayer properties. Using conventional MD simulations we are investigating the behavior of curcumin in DMPC, DPPC, and DOPC bilayers to compare with experimental measures of bilayer thickness, order, and hydrogen bonding.






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