Large stress asymmetries of lipid bilayers and nanovesicles generate lipid flip-flops and bilayer instabilities

Much effort has been devoted to lipid bilayers and nanovesicles with a compositional asymmetry between the two leaflets of the bilayer membranes. Here, we address another fundamental asymmetry related to lipid densities and membrane tensions. To avoid membrane rupture, the osmotic conditions must be adjusted in such a way that the bilayer membranes are subject to a relatively low bilayer tension. However, even for vanishing bilayer tension, the individual leaflets can still experience significant leaflet tensions if one leaflet is stretched whereas the other leaflet is compressed. Such a stress asymmetry between the two leaflets can be directly controlled in molecular dynamics simulations by the initial assembly of the lipid bilayers. This stress asymmetry is varied here over a wide range to determine the stability and instability regimes of the asymmetric bilayers. The stability regime shrinks with decreasing size and increasing membrane curvature of the nanovesicle. In the instability regimes, the lipids undergo stress-induced flip-flops with a flip-flop rate that increases with increasing stress asymmetry. The onset of flip-flops can be characterized by a cumulative distribution function that is well-fitted by an exponential function for planar bilayers but has a sigmoidal shape for nanovesicles. In addition, the bilayer membranes form transient non-bilayer structures that relax back towards ordered bilayers with a reduced stress asymmetry. Our study reveals intrinsic limits for the possible magnitude of the transbilayer stress asymmetry and shows that the leaflet tensions represent key parameters for the flip-flop rates.