We derive a mean-field free energy for the phase behavior of coupled bilayer leaflets, which is implicated in cellular processes and important to the design of artificial membranes. Our model accounts for amphiphile-level structural features, particularly hydrophobic mismatch, which promotes antiregistration, in competition with the direct transmidplane coupling usually studied, which promotes registration. We show that the phase diagram of coupled leaflets allows multiple metastable coexistences, and we illustrate the kinetic implications of this with a detailed study of a bilayer of equimolar overall composition. For approximate parameters estimated to apply to phospholipids, equilibrium coexistence is typically registered, but metastable antiregistered phases can be kinetically favored by hydrophobic mismatch. Thus, a bilayer in the spinodal region can require nucleation to equilibrate, in a novel manifestation of Ostwald's rule of stages. Our results provide a framework for understanding disparate existing observations in the literature, elucidating a subtle competition of couplings and a key role for phase-transition kinetics in bilayer phase behavior.

Characterizing the nanoscale dynamic organization within lipid bilayer membranes is central to our understanding of cell membranes at a molecular level. We investigate phase separation and communication across leaflets in ternary lipid bilayers, including saturated lipids with between 12 and 20 carbons per tail. Coarse-grained molecular dynamics simulations reveal a novel two-step kinetics due to hydrophobic mismatch, in which the initial response of the apposed leaflets upon quenching is to increase local asymmetry (antiregistration), followed by dominance of symmetry (registration) as the bilayer equilibrates. Antiregistration can become thermodynamically preferred if domain size is restricted below ∼20 nm, with implications for the symmetry of rafts and nanoclusters in cell membranes, which have similar reported sizes. We relate our findings to theory derived from a semimicroscopic model in which the leaflets experience a “direct” area-dependent coupling, and an “indirect” coupling that arises from hydrophobic mismatch and is most important at domain boundaries. Registered phases differ in composition from antiregistered phases, consistent with a direct coupling between the leaflets. Increased hydrophobic mismatch purifies the phases, suggesting that it contributes to the molecule-level lipid immiscibility. Our results demonstrate an interplay of competing interleaflet couplings that affect phase compositions and kinetics, and lead to a length scale that can influence lateral and transverse bilayer organization within cells.

We study the kinetics governing the attainment of inter-leaflet domain symmetry in a phase-separating amphiphilic bilayer. "Indirect" inter-leaflet coupling via hydrophobic mismatch can induce an instability towards a metastable pattern of locally asymmetric domains upon quenching from high temperature. This necessitates a nucleation step to form the conventional symmetric domains, which are favoured by a "direct" inter-leaflet coupling. We model the energetics for a symmetric domain to nucleate from the metastable state, and find that an interplay between hydrophobic mismatch and thickness stretching/compression causes the effective hydrophobic mismatch, and thus line tension, to depend on domain size. This leads to strong departure from classical nucleation theory. We speculate on implications for cell membrane rafts or clusters, whose size may be of similar magnitude to estimated critical radii for domain symmetry.

Cell division and death can be regulated by the mechanical forces within a tissue. We study the consequences for the stability and roughness of a propagating interface, by analysing a model of mechanically-regulated tissue growth in the regime of small driving forces. For an interface driven by homeostatic pressure imbalance or leader-cell motility, long and intermediate-wavelength instabilities arise, depending respectively on an effective viscosity of cell number change, and on substrate friction. A further mechanism depends on the strength of directed motility forces acting in the bulk. We analyse the fluctuations of a stable interface subjected to cell-level stochasticity, and find that mechanical feedback can help preserve reproducibility at the tissue scale. Our results elucidate mechanisms that could be important for orderly interface motion in developing tissues.

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