Details

Autor(en) / Beteiligte

• Cruz, Luis
• Urbanc, Brigita
• Borreguero, Jose M.
• Lazo, Noel D.
• Teplow, David B.
• Stanley, H. Eugene

Titel

Solvent and Mutation Effects on the Nucleation of Amyloid β-Protein Folding

Ist Teil von

• Proceedings of the National Academy of Sciences - PNAS, 2005-12, Vol.102 (51), p.18258-18263

Ort / Verlag

United States: National Academy of Sciences

Erscheinungsjahr

2005

Quelle

MEDLINE

Beschreibungen/Notizen

• Experimental evidence suggests that the folding and aggregation of the amyloid $\beta-protein$ (Aβ) into oligomers is a key pathogenetic event in Alzheimer's disease. Inhibiting the pathologic folding and oligomerization of Aβ 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 $A\beta, A\beta_{21-30}$, 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, $[Gln-22]A\beta_{21-30}$. 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 Aβ folds into pathologic structures.