Membrane flip-flop

Note that in this experimental set-up, the molar amount of lipids in the vesicle population equals the molar amount of DMPC in the MLs. During the incubation step DMPC and DSTAP, spontaneously percolate between both colloidal particles. However, for thermodynamical reasons, i.e., slow trans-membraneous flip-flop movements, only the outer leaflet of the ML coat and the outer shell of the vesicle membrane are involved in the exchange process (3, 13). As 2/3 of the total lipid contents is present in the outer layer of the vesicles and MLs, an equilibrium will be reached when 1/3 of the lipids has transferred. Thus, if the starting vesicles contain 10% DSTAP, ultimately, 3.33% arrives in the ML population. 

There is also inside-outside (transverse) asymmetry of the phospholipids. The choline-containing phospholipids (phosphatidylcholine and sphingomyelin) are located mainly in the outer molecular layer the aminophospholipids (phosphatidylserine and phos-phatidylethanolamine) are preferentially located in the inner leaflet. Obviously, if this asymmetry is to exist at all, there must be limited transverse mobility (flip-flop) of the membrane phospholipids. In fact, phospholipids in synthetic bilayers exhibit an extraordinarily slow rate of flip-flop the half-life of the asymmetry can be measured in several weeks. However, when certain membrane proteins such as the erythrocyte protein gly-cophorin are inserted artificially into synthetic bilayers, the frequency of phospholipid flip-flop may increase as much as 100-fold. 

Lipophilicity is intuitively felt to be a key parameter in predicting and interpreting permeability and thus the number of types of lipophilicity systems under study has grown enormously over the years to increase the chances of finding good mimics of biomembrane models. However, the relationship between lipophilicity descriptors and the membrane permeation process is not clear. Membrane permeation is due to two main components the partition rate constant between the lipid leaflet and the aqueous environment and the flip-flop rate constant between the two lipid leaflets in the bilayer [13]. Since the flip-flop is supposed to be rate limiting in the permeation process, permeation is determined by the partition coefficient between the lipid and the aqueous phase (which can easily be determined by log D) and the flip-flop rate constant, which may or may not depend on lipophilicity and if it does so depend, on which lipophilicity scale should it be based ... 

Regev, R. Eytan, G. D., Flip-flop of doxorubicin across erythrocyte and lipid membranes, Biochem. Pharmacol. 54, 1151-1158 (1997). 

Phospholipids, which are one of the main structural components of the membrane, are present primarily as bilayers, as shown by molecular spectroscopy, electron microscopy and membrane transport studies (see Section 6.4.4). Phospholipid mobility in the membrane is limited. Rotational and vibrational motion is very rapid (the amplitude of the vibration of the alkyl chains increases with increasing distance from the polar head). Lateral diffusion is also fast (in the direction parallel to the membrane surface). In contrast, transport of the phospholipid from one side of the membrane to the other (flip-flop) is very slow. These properties are typical for the liquid-crystal type of membranes, characterized chiefly by ordering along a single coordinate. When decreasing the temperature (passing the transition or Kraft point, characteristic for various phospholipids), the liquid-crystalline bilayer is converted into the crystalline (gel) structure, where movement in the plane is impossible. 

Lateral diffusion is in the plane of the membrane, and transverse (flip-flop) diffusion is perpendicular to the membrane (through the membrane). Lateral diffusion (in two dimensions) is fast, and transverse diffusion is slow (or nonexistent) except for gases (C02, NH3) and hydrophobic, uncharged, small molecules (such as cholesterol)... 

Sratton, D.L., Fadok, V.A., Richter, D.A., Kailey, J.M., Frasch, S.C., Nakamura, T. and Henson, P.M., 1999, Polyamine regulation of plasma membrane phosphohpid flip-flop during apoptosis. J. Biol. Chem., 274 28113-28120. 

Lipids and proteins can shift easily within one layer of a membrane, but switching between the two layers ( flip/flop") is not possible for proteins and is only possible with difficulty for lipids (with the exception of cholesterol). To move to the other side, phospholipids require special auxiliary proteins (translocators, flipases ). 

Flip-flop of lipids across membrane bilayers, PHOSPHOLIPID FLIP-FLOP "FLOG,"... 

Bennet, W.F.D., MacCallum, J.L., Hinner, M., Marrink, S.J., Tieleman, D.P. A molecular view of cholesterol flip-flop and chemical potential in different membrane environments. J. Am. Chem. Soc. 2009, in press. 

Rog, T., Stimson, L.M., Pasenkiewicz-Gierula, M., Vattulainen, I., Karttunen, M. Replacing the cholesterol hydroxyl group with the ketone group facilitates sterol flip-flop and promotes membrane fluidity. J. Phys. Chem. B 2008, 112, 1946-52. 

Vesicle size, bilayer fluidity, membrane permeability, microviscosity, ability to bind small molecules, suseeptibility to pore formation, flip-flop rates, extent of water penetration, lateral amphiphile diffusion, vesiele fusion, and kinetic medium effeets (some of which will be discussed briefly below) all depend on the paeking of... 

Y. Kobatake and H. Fujita, Flows through charged membranes. I. Flip-flop current vs voltage relation, J. Chem. Phys., 40 (1964), pp. 2212-2218. 

At physiological temperature, transbilayer—or flip-flop —diffusion of a lipid molecule from one leaflet of the bilayer to the other (Fig. ll-16a) occurs very slowly if at all in most membranes. Transbilayer movement requires that a polar or charged head group leave its... 

Flip-flop diffusion of lipids between the inner and outer leaflets of a membrane is very slow except when specifically catalyzed by flippases. 

Although phospholipids diffuse laterally in the plane of the bilayer and rotate more or less freely about an axis perpendicular to this plane, movements from one side of the bilayer to the other are a different matter. Diffusion across the membrane, a transverse, or flip-flop, motion, requires getting the polar head-group of the phospholipid through the... 

---