Registered and Antiregistered Phase Separation of Mixed Amphiphilic Bilayers

Abstract

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.

Undulations Drive Domain Registration from the Two Membrane Leaflets

“…That is, the current theory also explains the registration of domains that are induced by the adsorption of peripheral peptides (20) or scaffolding proteins (39). It avoids the artificial introduction of (thus far enigmatic) interactions at the membrane midplane (14,19) to explain registration and to rule out antiregistration.…”

“…However, measurements of interleaflet friction revealed the same mobility for long and short lipid molecules suggesting that there might not be permanent overhang (13). Nevertheless, the hypothesis about membrane midplane interaction is still en vogue, although, it is unclear 1) whether the liquid-disordered (L d ) domains and L o domains repel each other, or 2) whether the phenomenon is caused by attraction of the two L d domains and/or the two L o domains, or 3) what the underlying attractive or repulsive forces may generate (14,15). An alternative hypothesis with more mechanistic insight is that domain registration minimizes the line tension at the perimeter of the thicker L o phases (11): a small shift in the boundary between L d and L o domains in the two leaflets suffices to minimize the elastic deformations that arise from the hydrophobic mismatch between the two phases.…”

Effects of passive phospholipid flip-flop and asymmetric external fields on bilayer phase equilibria

“…The contour lines indicate where phospholipid chemical potentials of both leaflets are equal, µ t = µ b . B) "Pre flip-flop" partial phase diagram for times t < t f-f , obtained by drawing common tangent planes on f (φ t , φ b ) [1]. Equilibrium tie-lines (R-R, R-AR) and triangles (R-R-AR) are black, and metastable coexistences (AR-AR, AR-AR-R) are red.…”

“…[4,[25][26][27]. We describe our specific implementation of this approach [1,2,30] and the parameters used in the rest of the paper. In Section III we use this approach to develop a theory to describe the effects of flip-flop and external fields on phase behaviour.…”

“…1A, we use a semi-microscopic lattice model of coupled leaflets [1,2,30]. We emphasise, however, that a similar form of landscape also arises from a fully phenomenological approach [4,[25][26][27], and most of our findings here follow from very general considerations common to either case.…”