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

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Abstract
The major protein constituent of the deposits of Alzheimer's disease is the so-called amyloid β-peptide (Aβ) which was derived from proteolysis of a large transmembrane amyloid precursor protein. Some physicochemical and biological properties of the Aβ(1-42) peptide are described in this paper. Three functional areas of the soluble Aβ(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 α-helical structure which is stabilized by intramolecular hydrogen-bonding forces. The result is a loop-like molecule. The second lipophilic core has a β-sheet structure, and is able to form long-ranged, noncovalent, mainly hydrophobic forces with other β-sheets of Aβ peptides. The β-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 β-sheets by noncovalent interactions, blocking the associations between the individual Aβ peptides and preventing the formation of amyloid aggregates. © 1998 John Wiley & Sons, Inc. Med Res Rev, 18, No. 6, 403–430, 1998.