Interleaflet Coupling and Domain Registry in Phase-Separated Lipid Bilayers

Abstract

There is clear evidence of an interleaflet coupling in model lipid/cholesterol membranes exhibiting liquid-liquid phase separation. The strength of this coupling is quantified by the mismatch free energy, γ. We calculate it using a molecular mean-field model of a phase-separated lipid/cholesterol bilayer and obtain values that increase as the concentration of saturated lipids in the coexisting phases is increased. These values lie in the range 0.01-0.03 k(B)T/nm(2). We clarify the relationship between the interleaflet coupling and the extent of interleaflet alignment of liquid domains by analyzing a statistical mechanical model of coupled fluctuating domain interfaces. The model is solved exactly using the correspondence between statistical mechanics and quantum mechanics, yielding an expression for the characteristic size of fluctuations out of domain registry. This length scale depends only weakly on the strength of the interleaflet coupling and inevitably is only of the order of nanometers, which explains the experimental result that fluctuations out of domain registry have not been observed by optical microscopy.

Daptomycin inhibits cell envelope synthesis by interfering with fluid membrane microdomains

“…Thus, daptomycin has a dramatic effect on the liquid-order/disorder balance of the cell membrane. Several studies have shown that there is a coupling between the bilayer leaflets and that local disorder in one leaflet stimulates local disorder of the opposite leaflet (52)(53)(54). Thus, the distortion of lipids in the outer leaflet by daptomycin likely attracts fluid lipids in the inner leaflet as well.…”

Lipid Domain Co-localization Induced by Membrane Undulations

“…The molecular mean-field approach of Putzel et al (12), on the other hand, yields explicit predictions for the contributions of gauche bond energy, configurational entropy, and orientational interactions to L mol for flat membranes. Combining the results from these two complementary approaches should thus yield a predictive expression of the total interleaflet coupling, L ¼ L mol þ L fluct , which incorporates both molecular-scale and collective fluctuation effects.…”

“…Although the renormalization of the bending rigidity should only lead to small changes in L fluct (this is because k 0 À k R ( 3k B T ( k 0 for l(100 mm), the temperature dependence of k R for both the domain and background phases may offer a means to extract ' from experiments that quantify vesicle shape fluctuations (36)-and thus k R -over a range of temperatures. From a simulation perspective, on the other hand, the theoretical predictions presented in this article are amenable to verification via particle-based simulations of membrane systems, in which the elastic properties between the domains and the matrix phase are explicitly tuned, ' is extracted from simulated membrane undulation spectra (24), and L is measured from, e.g., out-of-alignment fluctuations (10,12).…”

“…To explain this observed registration between domains, several physical mechanisms have been proposed, such as cholesterol flip-flop and dynamic chain interdigitation (11) and complex interplay between chain entropic and energetic effects (12). As for the strength of the interleaflet coupling, L, theoretical predictions range from $ 1 k B T=nm 2 (11,13) to $ 0:01 k B T=nm 2 (12), while very recent experimental work employing a microfluidics approach in conjunction with a supported bilayer system has obtained a value of Lz0:016 k B T= nm 2 for a representative ternary lipid system (14). To put these values in perspective, as shown in (12), the characteristic width of the mismatched region resulting from out-of-alignment fluctuations is given by x t ¼ ½ðk B TÞ 2 =ðLtÞ 1=3 , where t $ 10 À12 N denotes the line tension between Ld/Lo domains away from a critical point (2).…”

“…To date, all existing theoretical work on the interleaflet coupling has focused on planar membranes (11)(12)(13), although one of the hallmark features of soft matter systems is their susceptibility to thermo-mechanical perturbations. A case in point is the development of membrane undulations at finite temperature, which in turn gives rise to algebraically decaying, fluctuation-induced interactions between membrane inclusions that are more rigid or softer than the background phase (15)(16)(17)(18)(19).…”