Molecular simulation of the primary and secondary structures of the Abeta(1-42)-peptide of Alzheimer's disease.

The major protein constituent of the deposits of Alzheimer's disease is the so-called amyloid beta-peptide (Abeta) which was derived from proteolysis of a large transmembrane amyloid precursor protein. Some physicochemical and biological properties of the Abeta(1-42) peptide are described in this paper. Three functional areas of the soluble Abeta(1-42) peptide were found: (i) a lipophilic region in the middle of the peptide (Lys16 to Ala21), (ii) a second lipophilic core at the end (Lys28 to Val40), and (iii) polarized and charged, solvent-exposed areas. Using molecule coordinates found experimentally by NMR-solution spectroscopy, subsequent Gasteiger-MM+ geometry optimization led to the result that the first lipophilic core has an alpha-helical structure which is stabilized by intramolecular hydrogen-bonding forces. The result is a loop-like molecule. The second lipophilic core has a beta-sheet structure, and is able to form long-ranged, noncovalent, mainly hydrophobic forces with other beta-sheets of Abeta peptides. The beta-strands run in an antiparallel direction. The aggregates are highly stable and ordered. The negatively charged, solvent-exposed residues are potential sites for a crosslinking with membrane-bound receptors. A perspective in drug research is the development of drugs that bind to individual beta-sheets by noncovalent interactions, blocking the associations between the individual Abeta peptides and preventing the formation of amyloid aggregates.