Journal
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
Volume 104, Issue 43, Pages 16880-16885Publisher
NATL ACAD SCIENCES
DOI: 10.1073/pnas.0703832104
Keywords
beta-turn; helix; pH-dependent; molecular dynamics; electrostatics
Categories
Funding
- NCRR NIH HHS [P41 RR012255, RR 12255] Funding Source: Medline
- NIGMS NIH HHS [R01 GM048807, GM 48807, GM 57513, R01 GM057513] Funding Source: Medline
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Growing evidence suggests that the beta-amyloid (A beta) peptides of Alzheimer's disease are generated in early endosomes and that small oligomers are the principal toxic species. We sought to understand whether and how the solution pH, which is more acidic in endosomes than the extracellular environment, affects the conformational processes of A beta. Using constant pH molecular dynamics simulations of two model peptides, A beta(1-28) and A beta(1042), we found that the folding landscape of A beta is strongly modulated by pH and is most favorable for hydrophobically driven aggregation at pH 6. Thus, our theoretical findings substantiate the possibility that A beta oligomers develop intracellularly before secretion into the extracellular milieu, where they may disrupt synaptic activity or act as seeds for plaque formation.
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