Figure 1.

Bilayers may separate into registered R or antiregistered AR phases, in which the two leaflets are locally approximately symmetric, or strongly asymmetric, respectively. (A) A semimicroscopic theoretical model includes competing direct (B) and indirect (J, hydrophobic mismatch) interleaflet couplings,²¹ which respectively favor transbilayer symmetry and asymmetry. (B) A schematic “leaflet–leaflet” free-energy landscape f(ϕ^t, ϕ^b) with an axis for each leaflet’s composition,¹⁸⁻²¹ which determines phase coexistences through the common tangent plane construction.²¹ Tie-lines (dashed) for R–R and AR–AR coexistences are sketched beneath the landscape. For the overall leaflet compositions simulated here R–R has the lowest bulk free energy, while AR–AR is metastable. Both R and AR demixing modes exist (curved arrows). (C) Schematic map of linear instability growth rates for R versus AR demixing modes, obtained from f(ϕ^t, ϕ^b) plus gradient terms for thickness or composition boundaries between domains.²¹ For a longer saturated lipid (5:0 PC) we expect the AR mode to grow fastest, leading to initial demixing into an AR–AR state. (D) The overall composition is a mixture of 3:5:2 molar ratios DLiPC:DnPC:cholesterol. (E) A snapshot after 10 μs of simulation showing how the lipids have separated into registered ordered and disordered phases (water is not shown). (F) Altering the number of beads in the tail of the saturated lipid relative to DPPC tunes the tail length mismatch with the unsaturated lipid, DLiPC.