Registered and antiregistered phase separation of mixed amphiphilic bilayers

We derive a mean-field free energy for the phase behaviour 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 (AR), in competition with the `direct' trans-midplane coupling usually studied, promoting registration (R). We show that the phase diagram of coupled leaflets allows multiple \textit{metastable} coexistences, then illustrate the kinetic implications 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 favoured 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, elucidating a subtle competition of couplings, and a key role for phase transition kinetics in bilayer phase behaviour.