Trans-monolayer coupling of fluid domains in lipid bilayers

Lipid membranes that exhibit fluid–fluid phase coexistence are widely studied as models for the physical state of lipids in raft-forming biomembranes. Yet, whereas model membranes are typically symmetric, biomembranes maintain different lipid compositions in their two leaflets. In the plasma membrane, only the extracellular but not the cytoplasmic leaf contains a raft-competent lipid mixture. This raises the question if a raft-like state in the extracellular layer is able to induce a similar state also on the cytoplasmic side. Recent studies have thus begun to investigate the problem of trans-monolayer domain coupling in model membranes. Experimental work on asymmetric membranes has revealed that a tendency to phase-separate in one leaf can induce phase separation on the other leaf. Conversely, the lack of such a tendency can prevent phase separation in the apposed leaf. The strength of the coupling between domains can be described by a composition-dependent surface tension or, for small compositional changes, by a single coupling constant. Theoretical work has demonstrated how the coupling constant affects the phase behavior of a binary membrane. We summarize previous experimental findings and modeling efforts. In addition, three possible physical mechanisms of trans-monolayer domain coupling are discussed: electrostatic coupling, cholesterol flip-flop, and dynamic chain interdigitation. We argue that dynamic chain interdigitation likely provides the main contribution to the coupling constant. The charges of acidic lipids tend to reduce the coupling constant – but the reduction is insignificant even at low salt content.