Premium
Molecular simulation of the primary and secondary structures of the Aβ(1‐42)‐peptide of Alzheimer's disease
Author(s) -
Mager Peter P.
Publication year - 1998
Publication title -
medicinal research reviews
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.868
H-Index - 130
eISSN - 1098-1128
pISSN - 0198-6325
DOI - 10.1002/(sici)1098-1128(199811)18:6<403::aid-med4>3.0.co;2-c
Subject(s) - antiparallel (mathematics) , peptide , chemistry , biophysics , intramolecular force , amyloid beta , beta sheet , transmembrane protein , protein secondary structure , proteolysis , stereochemistry , hydrogen bond , molecule , amyloid (mycology) , p3 peptide , protein structure , crystallography , receptor , alzheimer's disease , biochemistry , amyloid precursor protein , organic chemistry , enzyme , biology , inorganic chemistry , physics , quantum mechanics , magnetic field , medicine , disease , pathology
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.