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

  1. Author:
    Ma, B. Y.
    Nussinov, R.

  2. Author Address

    Sci Applicat Int Corp, Intramural Res Support Program, NCI, Frederick, MD 21702 USA Sci Applicat Int Corp, Lab Expt & Computat Biol, NCI, Frederick, MD 21702 USA Sci Applicat Int Corp, Intramural Res Support Program, NCI, Frederick, MD 21702 USA Tel Aviv Univ, Sackler Fac Med, Dept Human Genet, Sackler Inst Mol Med, IL-69978 Tel Aviv, Israel Nussinov R Sci Applicat Int Corp, Intramural Res Support Program, NCI, Frederick, MD 21702 USA
    1. Year: 2002
  2. Journal: Proceedings of the National Academy of Sciences of the United States of America
    1. 99
    2. 22
    3. Pages: 14126-14131
  4. Type of Article: Article
  1. Abstract:

    Previously, we have studied the minimal oligomer size of an aggregate amyloid seed and the mechanism of seed growth with a multilayer beta-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 beta-peptide (Abeta) fragments 16-22, 16- 35, and 10-35 (abbreviated Abeta(16-22), Abeta(16-35), and Abeta(10-35), respectively). Our simulations indicate that an antiparallel beta-sheet orientation is the most stable for the Abeta16-22, 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 Abeta(16-22) strands indicates a highly twisted fibril. Whereas the short Abeta(16-22) and Abeta(24-36) may exist in fully extended form, the linear parallel beta- sheets for Abeta(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 p-sheets with higher stability. An intra-strand salt-bridge (D23-K28) stabilizes the bent hairpin-like hook structure. The bent double-beta-sheet model for the Abeta(10-35) similarly offers oligomer stability.

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