Biological membranes show domain formation characterized by lateral inhomogeneities in chemical composition and physical properties. These domains seem to play important roles in signal transduction and membrane traffic. Furthermore, lipid domains are important in health and disease and make an interesting target for pharmacological approaches in cure and prevention of diseases such as Alzheimer, Parkinson, cardiovascular and prion diseases, systemic lupus erythematosus and HIV.

Among all techniques used to detect and characterize domains freeze-fracture electron microscopy (ff-em) is a forgotten one although it is a very powerful TEM technique to monitor membrane domains in a probe-free mode. Using this technique domain artifacts possibly initiated by probe molecules are avoided. Since the resolution of this replica technique is limited by the particle size of the Pt/C evaporation layer (in our hands 2 nm for periodical structures) we are able to study formation and transformation of lipid-, protein-, toxin-, as well as drug domains on a nano-resolution scale. The fact that during fracturing the fracture plane follows the area of weakest forces, allows insides into the hydrophobic center of lipid bilayer [1-3] as well as into the lipid/gas interface of lipid monolayer stabilizing gas bubbles [4].

Examples will be given for lipid domains in liposomal bilayer and their transformation by temperature, incorporation of amphiphilic drugs [5], and proteins. Furthermore, domain initiation by toxin and phage protein will be shown. Lipid-induced modulation of 2-D crystals of bacteriorhodopsin in liposomal bilayer will be shown as an extreme example for domain formation of membrane-spanning proteins [6-9]. Additionally, liquid ordered (Lo) domains will be shown recently detected in lipid monolayer, stabilizing hydrophobic gas bubbles [10].

[1] B. Sternberg, Liposome Technology, CRC Press I (1992) 363.

[2] B. Sternberg, Handbook Nonmedical Applications of Liposomes CRC Press (1996) 271.

[3] B. Sternberg, Medical Applications of Liposomes, Elsevier (1998) 395.

[4] C. Brancewicz et al. J. Disp. Sci. & Techn. 27:5 (2006) 761.

[5] K. Merz and B. Sternberg J. Drug Targ. 2 (1994) 411.

[6] B. Sternberg et al. Biochim. Biophys. Acta 980 (1989) 117.

[7] B. Sternberg et al. Biochim. Biophys. Acta 1108 (1992) 21.

[8] B. Sternberg et al. J. Struc. Biol. 110 (1993) 196.

[9] A. Watts et al. New Compreh. Biochem. 25 (1993) 351.

[10] M. A. Borden at al. Langmuir 22 (2006) 4291.