Induced asymmetries in membranes

Abstract

Lipid asymmetry in plasma membrane of eukaryotes is ubiquitous. The first measurements reported compositional asymmetry: phosphatidylethanolamine and phosphatidylserine are mostly on the cytoplasmic leafet, while phosphatidylcholine and sphingomyelin are mostly on the exoplasmic leaflet. More recent experiments using lipidomics have evidenced the presence of saturation asymmetry between the two leaflets. A question that naturally arises is why such an asymmetry? To complicate matters, it is still largely unknown in which leaflet cholesterol lies. Here, we use chemical potentials to mimic flippase proteins responsible for maintenance of compositional asymmetry in silico. We show that saturation asymmetry naturally arises as a byproduct of phospholipid number asymmetry and sphingomyelin contents, thereby showing that some reported asymmetries may naturally result from others and do not necessarily require being externally driven. We also show that plasmalogen lipids' tendency to be highly unsaturated is also natural. Additionally, we tackle the problem of cholesterol and show that, while it is influenced by all asymmetries, the resulting cholesterol asymmetry tends to be fairly mild.

Figure 1

Transformations between glycerophospholipids during simulations in the MARTINI coarse-grained force field. (A) Glycerophospholipid heads, glycerol shown in purple, phosphate group in yellow, and esterified moiety in blue. The esterified moeity can either be a P₅ bead (serine), Q₀ bead (choline), or Q_d bead (ethanolamine). Plasmalogens, characterized by an ether linkage, are represented by a C₅ bead on the glycerol linker due to higher hydrophobicity than esters. We forbid PS plasmalogens by numerically disabling any transition to such lipids. Changes in charges are uncompensated, leading to varying bilayer charges over the course of simulations. (B) Lipid tails, unsaturations located at dark gray beads. Beads corresponding to saturated bonds are represented by C₁ beads, whereas unsaturations correspond to C₃ beads. Tails are free to change nature over time; left: sn-1-palmitoyl-sn-2-dihomo-$\gamma$-linoleoyl-, right: sn-1-oleoyl-sn-2-all-cis-8,11,14,17-eicosatetraenoyl-. Not all combinations and lipid unsaturation positions are allowed; see supporting material for details. To see this figure in color, go online.

Figure 2

Ratio of PC to PE contents in the cytoplasmic leaflet for bilayers incorporating either PS (A) or PEp (B) in their cytoplasmic leaflet. Color indicates phospholipid number asymmetry. The x axis indicates overall proportion in the cytoplasmic leaflet, including cholesterol. All lipids are free to change their acyl tails. Only PC and PE are free to exchange their headgroups. To see this figure in color, go online.

Figure 3

Asymmetries observed in SM/PC/PE bilayers as a function of exoplasmic SM contents and number asymmetry. Bilayers incorporate 20% cholesterol. (A) Cholesterol asymmetry and (B) mean PC unsaturation levels. Color indicates phospholipid number asymmetry. The x axis indicates overall proportion of SM in the exoplasmic leaflet, including cholesterol. PC and PE lipids are free to change their acyl tails, whereas SM is constrained to a palmitoyl tail (C16:0). PC and PE are free to exchange their headgroups. To see this figure in color, go online.

Figure 4

Properties of bilayers incorporating many types of lipids. (A) Representative lipid composition for $\delta =0$ as a function of unsaturation levels (indicated by color). Red (blue) bars denote exoplasmic (cytoplasmic) lipids. Note that exoplasmic SM and overall cholesterol compositions are constrained. (B) Enrichment of exoplasmic PC as a function of unsaturation levels and phospholipid number asymmetry for a membrane incorporating 240 SM lipids. Color indicates phospholipid number asymmetry. Lipids with less than three unsaturations typically represent less than 0.5% of the overall population levels and are therefore not shown here. In this simulation, phospholipids are free to change acyl tails, whereas SM molecules always have a palmityol tail. Phospholipids are free to exchange headgroups. To see this figure in color, go online.