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

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Abstract
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 Aβ16–22, Aβ16–35, and Aβ10–35, respectively). Our simulations indicate that an antiparallel β-sheet orientation is the most stable for the Aβ16–22, 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 Aβ16–22 strands indicates a highly twisted fibril. Whereas the short Aβ16–22 and Aβ24–36 may exist in fully extended form, the linear parallel β-sheets for Aβ16–35 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 Aβ10–35 similarly offers oligomer stability.