Registered and antiregistered phase separation of mixed amphiphilic bilayers

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.