The three-dimensional structure of the Alzheimer's disease Abeta1-42 peptide was predicted by sequence homology, threading approaches and by experimental observations. The Abeta molecule displayed a Greek key motif with four antiparallel beta-strands. To shield thermodynamically unfavorable domains, two Abeta 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 A 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 Abeta peptides. These characteristics are of functional significance in terms of Abeta-topology, fibril formation and cytotoxicity. The model also suggests that Abeta 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.