The mechanism of collapse of heterogeneous lipid monolayers

Abstract

Collapse of homogeneous lipid monolayers is known to proceed via wrinkling/buckling, followed by folding into bilayers in water. For heterogeneous monolayers with phase coexistence, the mechanism of collapse remains unclear. Here, we investigated collapse of lipid monolayers with coexisting liquid-liquid and liquid-solid domains using molecular dynamics simulations. The MARTINI coarse-grained model was employed to simulate monolayers of ∼80 nm in lateral dimension for 10-25 μs. The monolayer minimum surface tension decreased in the presence of solid domains, especially if they percolated. Liquid-ordered domains facilitated monolayer collapse due to the spontaneous curvature induced at a high cholesterol concentration. Upon collapse, bilayer folds formed in the liquid (disordered) phase; curved domains shifted the nucleation sites toward the phase boundary. The liquid (disordered) phase was preferentially transferred into bilayers, in agreement with the squeeze-out hypothesis. As a result, the composition and phase distribution were altered in the monolayer in equilibrium with bilayers compared to a flat monolayer at the same surface tension. The composition and phase behavior of the bilayers depended on the degree of monolayer compression. The monolayer-bilayer connection region was enriched in unsaturated lipids. Percolation of solid domains slowed down monolayer collapse by several orders of magnitude. These results are important for understanding the mechanism of two-to-three-dimensional transformations in heterogeneous thin films and the role of lateral organization in biological membranes. The study is directly relevant for the function of lung surfactant, and can explain the role of nanodomains in its surface activity and inhibition by an increased cholesterol concentration.

Figure 1

Monolayer morphologies at low surface tensions, view from air (top panel), and side view (bottom panel). The mixture of 3:1:1 DPPC/POPG/DOPC at 290 K and 0 mN/m (a), at 270 K and 0 mN/m (b), and the mixture of 5:3:4 DPPC/DOPC/cholesterol at 290 K and 5 mN/m (c); final structures are shown. The following color scheme is used: (green) DPPC, (yellow) POPG, (orange) DOPC, and (purple) cholesterol; water not shown. To see this figure in color, go online.

Figure 2

The mixture of 5:3:4 DPPC/DOPC/cholesterol at 290 K at the equilibrium surface tension of 22 mN/m (a–c) and minimum surface tension of 5 mN/m (d–f). Monolayer view from air (a and d), surface profile (nm) obtained with a binary filter (b and e), and mean curvature (nm⁻¹) (c and f) are shown. Color scheme for panels a and d as in Fig. 1. To see this figure in color, go online.

Figure 3

Formation of bilayer folds for different monolayer morphologies. The mixture of 3:1:1 DPPC/POPG/DOPC at 290 K and 0 mN/m (a), at 270 K and −1 mN/m (b), and the mixture of 5:3:4 DPPC/DOPC/cholesterol at 290 K and 2 mN/m (c). View from air (top panel), and side view (bottom panel); (semitransparent, top view) monolayer in the top view; (opaque) bilayer fold; (black ellipses) folds. Color scheme as in Fig. 1. To see this figure in color, go online.

Figure 4

Fold growth for the 3:1:1 DPPC/POPG/DOPC mixture at 290 K and 0 mN/m (a–c) and for the 5:3:4 DPPC/DOPC/cholesterol mixture at 290 K and 2 mN/m (d–f). Once the folds are formed (images a and d correspond to Fig. 3, a and c), they grow in amplitude (b and e) and bend (c and f) to form a semivesicle. Upside-down view from water (folds grow into water); folds are sliced for clarity, with color scheme as in Fig. 1. To see this figure in color, go online.

Figure 5

Monolayer in equilibrium with bilayers. The 3:1:1 DPPC/POPG/DOPC mixture at 270 K at the equilibrium surface tension for smaller (a–c) and larger (d–f) monolayer compression is shown; top view (a and d), cross-section view (b and e), and upside-down view (c and f) with sliced bilayers. Color scheme as in Fig. 1. To see this figure in color, go online.

Figure 6

Monolayer in equilibrium with bilayers. The 5:3:4 DPPC/DOPC/cholesterol mixture at 290 K at the equilibrium surface tension for smaller (a–c) and larger (d–f) monolayer compression is shown; top view (a and d), cross-section view (b and e), and upside-down view (c and f) with sliced bilayers. Color scheme as in Fig. 1. To see this figure in color, go online.