The Unique Roles of Hybrid Lipids in Lipid Membrane Domain Size and Order

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Hybrid lipids (HL) are phospholipids with one saturated and one unsaturated chains. Although it is believed that hybrid lipids can act as linactants (i.e., 2D surfactants) in cell membranes to reduce line tension of lipid domains, as a group, their fundamental roles in membrane heterogeneity have not yet been systematically investigated. In this study, three hybrid lipids of different degrees of chain unsaturation (i.e., 16:0-18:1PC (POPC), 16:0-18:2PC (PLPC), and 16:0-20:4PC (PAPC)) are compared in their abilities to alter the composition, order and compactness of lipid domains. The liquid-ordered and liquid-disordered (Lo+Ld) phase boundaries of HL/di18:0PC(DSPC)/cholesterol systems were determined from giant unilamellar vesicles (GUV). We found that the Lo and Ld lipid domains in PAPC/DSPC/CHOL and PLPC/DSPC/CHOL mixtures are micron-sized, and only POPC/DSPC/CHOL system has nanoscopic domains. The results show that some poly-unsaturated HLs essentially behave like the double-unsaturated di18:1PC (DOPC), and the mono-unsaturated POPC clearly displays both properties of unsaturated lipid and linactant. The obtained phase boundaries indicate that both POPC and PLPC have significant partition in the Lo phases. Our MD simulations reveal that these hybrid lipids decrease the order and compactness of Lo domains. Thus, hybrid lipids distinguish themselves from other lipids in this combined “partitioning and loosening” ability in Lo domains, and this ability could facilitate membrane proteins to partition into lipid-raft-like domains in biomembranes. Our line tension measurement and Monte Carlo simulation both show that even in the best cases, HLs are weak linactants with only modest ability in reducing line tension. Furthermore, the reduction is through two separated mechanisms: one through reducing the compositional differences of Lo and Ld domains, and the other through weak linactant action.