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.
|Number of pages||6|
|Journal||Proceedings of the National Academy of Sciences of the United States of America|
|State||Published - 29 Oct 2002|
- Amyloid conformation
- Double-layered sheets
- Molecular dynamics simulation
- Protein folding