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Solvent and mutation effects on the nucleation of amyloid [beta]-protein folding
- Source :
- Proceedings of the National Academy of Sciences of the United States. Dec 20, 2005, Vol. 102 Issue 51, p18258, 6 p.
- Publication Year :
- 2005
-
Abstract
- Experimental evidence suggests that the folding and aggregation of the amyloid [beta]-protein (A[beta]) into oligomers is a key pathogenetic event in Alzheimer's disease. Inhibiting the pathologic folding and oligomerization of A[beta] 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 A[beta], A[[beta].sub.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]A[[beta].sub.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 A[beta] folds into pathologic structures. molecular dynamics | Alzheimer's disease | hydrophobic interactions | salt bridges
Details
- Language :
- English
- ISSN :
- 00278424
- Volume :
- 102
- Issue :
- 51
- Database :
- Gale General OneFile
- Journal :
- Proceedings of the National Academy of Sciences of the United States
- Publication Type :
- Academic Journal
- Accession number :
- edsgcl.140661962