期刊
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
卷 102, 期 51, 页码 18258-18263出版社
NATL ACAD SCIENCES
DOI: 10.1073/pnas.0509276102
关键词
molecular dynamics; Alzheimer's disease; hydrophobic interactions; salt bridges
资金
- NIA NIH HHS [AG18921, AG23661, R01 AG018921, R21 AG023661] Funding Source: Medline
- NINDS NIH HHS [NS44147, NS38328, R01 NS038328, R01 NS044147] Funding Source: Medline
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(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; (h) 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.
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