Stabilities and conformations of Alzheimer's β-amyloid peptide oligomers (Aβ(16)(–)(22), Aβ(16–35), and Aβ(10)(–)(35)): Sequence effects

Previously, we have studied the minimal oligomer size of an aggregate amyloid seed and the mechanism of seed growth with a multilayer β-sheet model. Under high temperature simulation conditions, our approach can test the stability of possible amyloid forms. Here, we report our study of oligomers of Alzheimer's amyloid β-peptide (Aβ) fragments 16–22, 16–35, and 10–35 (abbreviated Aβ(16–22), Aβ(16–35), and Aβ(10–35), respectively). Our simulations indicate that an antiparallel β-sheet orientation is the most stable for the Aβ(16–22), in agreement with a solid state NMR-based model [Balbach, J. J., Ishii, Y., Antzutkin, O. N., Leapman, R. D., Rizzo, N. W., et al. (2000) Biochemistry 39, 13748–13759]. A model with twenty-four Aβ(16–22) strands indicates a highly twisted fibril. Whereas the short Aβ(16–22) and Aβ(24–36) may exist in fully extended form, the linear parallel β-sheets for Aβ(16–35) appear impossible, mainly because of the polar region in the middle of the 16–35 sequence. However, a bent double-layered hairpin-like structure (called hook) with the polar region at the turn forms parallel β-sheets with higher stability. An intra-strand salt-bridge (D23-K28) stabilizes the bent hairpin-like hook structure. The bent double-β-sheet model for the Aβ(10–35) similarly offers oligomer stability.