In silico study of full-length amyloid β 1-42 tri- and penta-oligomers in solution

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 Aβ _1-42 aggregates in solution to their stability and conformational dynamics. We found that our models are stable at a temperature of 310 K, and converge toward an interdigitated side-chain packing for intermolecular contacts within the two β-sheet regions of the aggregates: β₁ (residues 18-26) and β₂ (residues 31-42). MD simulations reveal that the /3-strand twist is a characteristic element of Aβ-aggregates, permitting a compact, interdigitated packing of side chains from neighboring β-sheets. The β₂ portion formed a tightly organized β-helix, whereas the β₁ portion did not show such a firm structural organization, although it maintained its β-sheet conformation. Our simulations indicate that the hydrophobic core comprising the β₂ portion of the aggregate is a crucial stabilizing element in the Aβ aggregation process. On the basis of these structure-stability findings, the β₂ portion emerges as an optimal target for further antiamyloid drug design.