Send to:

Choose Destination
See comment in PubMed Commons below
Proc Natl Acad Sci U S A. 2005 Dec 20;102(51):18258-63. Epub 2005 Dec 9.

Solvent and mutation effects on the nucleation of amyloid beta-protein folding.

Author information

  • 1Center for Polymer Studies and Department of Physics, Boston University, Boston, MA 02215, USA.


Experimental evidence suggests that the folding and aggregation of the amyloid beta-protein (Abeta) into oligomers is a key pathogenetic event in Alzheimer's disease. Inhibiting the pathologic folding and oligomerization of Abeta could be effective in the prevention and treatment of Alzheimer's disease. Here, using all-atom molecular dynamics simulations in explicit solvent, we probe the initial stages of folding of a decapeptide segment of Abeta, Abeta(21-30), shown experimentally to nucleate the folding process. In addition, we examine the folding of a homologous decapeptide containing an amino acid substitution linked to hereditary cerebral hemorrhage with amyloidosis-Dutch type, [Gln-22]Abeta(21-30). We find that: (i) when the decapeptide is in water, hydrophobic interactions and transient salt bridges between Lys-28 and either Glu-22 or Asp-23 are important in the formation of a loop in the Val-24-Lys-28 region of the wild-type decapeptide; (ii) in the presence of salt ions, salt bridges play a more prominent role in the stabilization of the loop; (iii) in water with a reduced density, the decapeptide forms a helix, indicating the sensitivity of folding to different aqueous environments; and (iv) the "Dutch" peptide in water, in contrast to the wild-type peptide, fails to form a long-lived Val-24-Lys-28 loop, suggesting that loop stability is a critical factor in determining whether Abeta folds into pathologic structures.

[PubMed - indexed for MEDLINE]
Free PMC Article
PubMed Commons home

PubMed Commons

How to join PubMed Commons

    Supplemental Content

    Full text links

    Icon for HighWire Icon for PubMed Central
    Loading ...
    Write to the Help Desk