Lipid flip-flop

Gurtovenko, A.A., Vattulainen, I. Molecular mechanism for lipid flip-flops. J. Phys. Chem. B 2007, 111, 13554-59. 

All dynamic events are not so rapid, however. Lipid flip-flop, in which a lipid translocates from one leaflet to another in a membrane, is usually a profoundly slow process and occurs in a time scale of minutes or even hours. As for the longest time scale associated with biological lipid systems, the typical life time of a cell ranges from a few days to several months, which depends on the tissue type. 

Figure 4.8 Comb-shaped polyacrylate with hydrophobic side-chains integrates vesicle membranes, but hardly disturbs its ordering. Only melting of the membrane and or neutralization of the acrylate carboxylate group produces strong local disturbances. The polymer now promotes lipid flip-flops. ...

Intermembrane exchange Trans bilayer movement of amphiphilic solutes Lipid flip-flop... 

The cylinder stretching protocol appears to work very well for simple solvent-free membrane models [111, 113, 114], but with more refined models this method suffers from two drawbacks, both related to the equifibration of a chemical potential. First, the cylinder separates the simulation volume into an inside and an outside. If solvent is present, its chemical potential must be the same in these two regions, but for more highly resolved models the solvent permeability through the bilayer is usually too low to ensure automatic relaxation. Second, the chemical potential of lipids also has to be the same in the two bilayer leaflets, and again for more refined models the lipid flip-flop rate tends to be too low for this to happen spontaneously. 

Early examples of synthetic flippases were lipidated polymers, which used bilayer distortion to bring about lipid flip-flop. In contrast to these mechanical flippases, synthetic species that apply the principles of molecular recognition to create phospholipid complexes capable of transverse diffusion have been shown to enhance lipid flip-flop in model membrane systems. Boon and Smith generated asymmetric bilayers by adding synthetic NBD phospholipids to the outer leaflet of POPC vesicles and then determined the rate of flip-flop to the inner leaflet... 

Lipid flip-flop Movement of an amphiphile from one leaflet of a bilayer to the opposing leaflet. 

Moreover, properties such as lipid lateral diffusion, lipid flip/flop, membrane elasticity and surface tension can be heavily biased in MD simulations by too small boundaries. The study in ref. 68 reported a model made of over 60 different lipid types, in a stoichiometric ratio compatible to that experimentally determined using lipidomics approaches, for a total of 20 000 lipid molecules, and simulated for 40 microseconds using coarse-grained potentials. 

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