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Molecular dynamics simulations of Alzheimer A beta(40) elongation and lateral association

  1. Author:
    Zheng, J.
    Ma, B. Y.
    Chang, Y.
    Nussinov, R.

  2. Author Address

    Zheng, Jie] Univ Akron, Dept Chem & Biomol Engn, Akron, OH 44325 USA. [Ma, Buyong, Nussinov, Ruth] NCI, Basic Res Program, SAIC Frederick Inc, Ctr Canc Res Nanobiol Program, Frederick, MD 21702 USA. [Chang, Yung] Chung Yuan Christian Univ, Res & Dev Ctr Membrane Technol, Tao Yuan 320, Taiwan. [Chang, Yung] Chung Yuan Christian Univ, Dept Chem Engn, Tao Yuan 320, Taiwan. [Nussinov, Ruth] Tel Aviv Univ, Sackler Sch Med, Sackler Inst Mol Med, Dept Human Genet & Mol Med, IL-69978 Tel Aviv, Israel.
    1. Year: 2008
  2. Journal: Frontiers in Bioscience
    1. 13
    2. Pages: 3919-3930
  4. Type of Article: Article
  1. Abstract:

    Amyloid-beta (A beta) peptides can elongate in the fibril axis and associate in the lateral direction. We present detailed atomic A beta models with different in-register intermolecular beta-sheet-beta-sheet associations. We probe structural stability, conformational dynamics, and association force of A beta oligomers with various sizes and structures for both wild-type and mutated sequences using molecular dynamics (MD) simulations. MD simulations show that an A beta oligomer that is laterally associated through the C-terminal-C-terminal interface is energetically more favorable than other oligomers with the N-terminal-N- terminal and C-terminal-N-terminal interfaces. We further develop a simple numerical model to describe the kinetics of A beta aggregation process by considering fibril elongation and lateral association using a Monte Carlo algorithm. Kinetic data suggest that fibril elongation and lateral association are mutually competitive. Single-point mutations of Glu22 or Met35 at the interfaces have profound negative effects on intermolecular beta-sheet-beta-sheet association. These disease-related mutants (E22K, E22Q, and M35O) display more flexible structures, weaker lateral association, and stronger elongation tendencies than the wild type, suggesting that amyloid oligomerization and neurotoxicity might be linked to fibril longitudinal growth.

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External Sources

  1. PMID: 18508486

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