Proton and carbon-13 nmr spectra of unsonicated lipid bilayers and biological membranes are generally dominated by strong proton–proton and proton–carbon dipolar interactions. As a result the spectra contain a large number of overlapping resonances and are rather difficult to analyse. Nevertheless, important information on the structure and dynamic behaviour of lipid systems has been provided by these techniques (Wennerström & Lindblom, 1977).

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Protein molecules in solution or in protein crystals are characterized by rather well-defined structures in which α-helical regions, β-pleated sheets, etc., are the key features. Likewise, the double helix of nucleic acids has almost become the trademark of molecular biology as such. By contrast, the structural analysis of lipids has progressed at a relatively slow pace. The early X-ray diffraction studies by V. Luzzati and others firmly established the fact that the lipids in biological membranes are predominantly organized in bilayer structures (Luzzati, 1968). V. Luzzati was also the first to emphasize the liquid-like conformation of the hydrocarbon chains, similar to that of a liquid paraffin, yet with the average orientation of the chains perpendicular to the lipid–water interface. This liquid–crystalline bilayer is generally observed in lipid–water systems at sufficiently high temperature and water content, as well as in intact biological membranes under physiological conditions (Luzzati & Husson, 1962; Luzzati, 1968; Tardieu, Luzzati & Reman, 1973; Engelman, 1971; Shipley, 1973). In combination with thermodynamic and other spectroscopic observations these investigations culminated in the formulation of the fluid mosaic model of biological membranes (cf. Singer, 1971). However, within the limits of this model the exact nature of lipid conformation and dynamics was immaterial, the lipids were simply pictured as circles with two squiggly lines representing the polar head group and the fatty acyl chains, respectively. No attempt was made to incorporate the well-established chemical structure into this picture. Similarly, membrane proteins were visualized as smooth rotational ellipsoids disregarding the possibility that protruding amino acid side-chains and irregularities of the backbone folding may create a rather rugged protein surface.

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The beta-amyloid peptide beta AP(1-40), a 40-amino acid residues peptide, is one of the major components of Alzheimer's amyloid deposits. beta AP(1-40) exhibits only a limited solubility in aqueous solution and undergoes a concentration-dependent, cooperative random coil reversible beta-structure transition for Cpep > 10 microM [Terzi, E., Hölzemann, G., and Seelig, J. (1995) J. Mol. Biol. 252, 633-642]. In the presence of acidic lipid, the equilibrium is shifted further toward beta-structured aggregates. We have now characterized the lipid-peptide interaction using circular dichroism (CD) spectroscopy, lipid monolayers, and deuterium and phosphorus-31 solid-state nuclear magnetic resonance (NMR). CD spectroscopy revealed a distinct interaction between beta AP(1-40) and negatively charged unilamellar vesicles. In addition to the random coil reversible beta-structured aggregate equilibrium at low lipid-to-peptide (L/P) ratios, a beta-structure -->alpha-helix transition was observed at L/P > 55. beta AP(1-40) was found to insert into acidic monolayers provided the lateral pressure was low (20 mN/m). The extent of incorporation increased distinctly with the content of acidic lipid in the monolayer. However, at a lipid packing density equivalent to that of a bilayer (lateral pressure> or = 32 mN/m), no insertion of beta AP(1-40) was observed. The lipid molecular structure in the presence of beta AP(1-40) was studied with NMR. Phosphatidylcholine (PC) was selectively deuterated at the choline headgroup and at the cis-double bond of the oleic acyl chain and mixed with phosphatidylglycerol (PG). Phosphorus-31 NMR showed that the lipid phase retained the bilayer structure at all lipid-to-protein ratios. Deuterium NMR revealed no change in the headgroup conformation of the choline moiety or in the flexibility and ordering of the hydrocarbon chains upon the addition of beta AP-(1-40). It can be concluded that beta AP(1-40) binds electrostatically to the outer envelope of the polar headgroup region without penetrating between the polar groups. The data suggest a new mechanism of helix formation induced by the proper alignment of five positive charges of beta AP(1-40) on the negatively charged membrane template.