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

摘要

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.