Amyloid oligomers are considered to play causal roles in the pathogenesis of amyloid-related degenerative diseases including Alzheimer's disease. Using MD simulation techniques, we explored the contributions of the different structural elements of trimeric and pentameric full-length A beta(1-42) aggregates in solution to their stability and conformational dynamics. We found that Our models are stable at a temperature of 3 10 K, and converge toward an interdigitated side-chain packing for intermolecular contacts within the two beta-sheet regions of the aggregates: beta(1) (residues 18-26) and beta(2) (residues 31-42). MD simulations reveal that the beta-strand twist is a characteristic element of A beta-aggregates, permitting a compact, interdigitated packing of side chains from neighboring beta-sheets. The beta(2) portion formed a tightly organized beta-helix, whereas the beta(1) portion did not show such a firm Structural organization, although it maintained its beta-sheet conformation. Our simulations indicate that the hydrophobic core comprising the beta(2) portion of the aggregate is a crucial stabilizing element in the A beta aggregation process. On the basis of these structure-stability findings, the beta(2) portion emerges as an optimal target for further antiamyloid drug design.