Key Molecular Requirements for Raft Formation in Lipid/Cholesterol Membranes

Abstract

The lipid mixture of DPPC (saturated lipid)/DUPC (unsaturated lipid)/CHOL (cholesterol) is studied with respect to its ability to form liquid-ordered and liquid-disordered phases. We employ coarse-grained simulations with MARTINI force field. All three components are systematically modified in order to explore the relevant molecular properties, leading to phase separation. Specifically, we show that the DPPC/DUPC/CHOL system unmixes due to enthalpic DPPC-DPPC and DPPC-CHOL interactions. The phase separation remains unchanged, except for the formation of a gel phase at long times after decreasing the conformational degrees of freedom of the unsaturated DUPC. In contrast, the phase separation can be suppressed by softening the DPPC chains. In an attempt to mimic the ordering and unmixing effect of CHOL the latter is replaced by a stiff and shortened DPPC-like lipid. One still observes phase separation, suggesting that it is mainly the rigid and planar structure of CHOL which is important for raft formation. Addition of an extra bead to the head of CHOL has no notable impact on the phase separation of the system, supporting the irrelevance of the Umbrella model for the phase separation. Reduction of the conformational entropy of CHOL by stiffening its last bead results in a significant increase of the order of the DPPC/CHOL domain. This suggests that the conformational entropy of CHOL is important to prohibit the gelation process. The interleaflet interactions as mediated by the terminal molecular groups seem to have a strong impact on the possibility of a subsequent gelation process after phase separation.

Multiscale Modeling of Four-Component Lipid Mixtures: Domain Composition, Size, Alignment, and Properties of the Phase Interface

“…This is in agreement with previous studies of bilayer mixtures that show domain alignment is greater for larger domains. 25,54,61 We therefore conclude that interleaflet domain alignment in the quaternary system DPPC/PUPC/DUPC/chol is significantly affected by intraleaflet domain size, and in turn ρ.…”

“…61,62 This likely governs the quaternary system behavior as well. The unsaturated beads of DUPC and PUPC mix unfavorably with chol and with the saturated beads of DPPC.…”

Vertical ordering sensitivity of solid supported DPPC membrane to alamethicin and the related loss of cell viability

“…The results of the comparison reported above could have some biomedical relevance if we consider that the lecithin DPPC was of major importance for the lipid raft formation [29]. Indeed, the existence of such liquid-ordered lipid domains was recently highlighted in much of the plasma membrane in the live HeLa cells [59].…”

“…DPPC is an abundant and common structural plasma membrane lipid implicated in forming biologically relevant separate lipid phases [29]. Depending on temperature, DPPC bilayers exhibit three different structures of biological interest, namely a gel phase (L β ) (T b 35°C), with an overall ordered hydrocarbon chain arrangement, a liquid-crystalline phase (L α ) (T ≥ 42°C) and a ripple phase (P β ) (35 ≤ T b 42°C).…”

The Ras–Membrane Interface: Isoform-Specific Differences in the Catalytic Domain

“…In addition, glycolipids and cholesterol constitute up to one third of the total membrane lipid population (24). Recent evidence proposed that the rigid and planar cholesterol molecules that induce packing of fully saturated aliphatic chains help maintain a liquid-ordered (l o ) phase commonly referred to as a lipid raft (25). Contrastingly, in the presence of low cholesterol levels, lipids with unsaturated aliphatic chains cannot pack as tightly and tend to localize in nonordered (l d ) regions of the membrane (26), leading to a diverse membrane landscape of lipid raft "islands" floating in a sea of loosely packed lipids.…”