Molecular modeling of the Aβ1-42 peptide from Alzheimer's disease

The three-dimensional structure of the Alzheimer's disease A beta 1-42 peptide was predicted by sequence homology, threading approaches and by experimental observations. The A beta molecule displayed a Greek key moth with four antiparallel beta-strands. To shield thermodynamically unfavorable domains, two A beta molecules interact with each other to generate a beta-barrel structure with a hydrophilic surface and a hydrophobic core. The N-terminal domains of the dimer form crevices into which the non-polar C-termini are accommodated to yield a globular structure 27X32 Angstrom in diameter. Alternatively, the C-terminal domains of two opposing dimers could be extended to form an antiparallel beta-sheet, The stacking of these building blocks generates a helical protofilament. To create a thermodynamically more favorable structure, three protofilaments associate into a right-handed triple helix with a hydrophobic beta-sheet completely surrounded by the hydrophilic beta-barrels made of residues 1-28. Two triple helical strands can further associate into a right-handed amyloid filament. Although our model did not meet all the expected criteria, it nevertheless exhibited a series of naturally disposed structural features, revealed by other biophysical studies utilizing synthetic A beta peptides, These characteristics are of functional significance in terms of A beta-topology, fibril formation and cytotoxicity, The model also suggests that A beta may not exist in a thermodynamically stable conformation, but rather as an ensemble of metastable dimeric structures some of which are capable of generating an extended C-terminal antiparallel beta-sheet essential in the promotion of fibrillogenesis.