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BIOLOGICAL SCIENCES / BIOPHYSICS
Linking folding with aggregation in Alzheimer's β-amyloid peptides
Department of Molecular Biology, TPC6, Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, CA 92037
Edited by Robert L. Baldwin, Stanford University Medical Center, Stanford, CA, and approved September 5, 2007 (received for review April 16, 2007)
Growing evidence suggests that the β-amyloid (Aβ) 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 Aβ. Using constant pH molecular dynamics simulations of two model peptides, Aβ(1–28) and Aβ(10–42), we found that the folding landscape of Aβ is strongly modulated by pH and is most favorable for hydrophobically driven aggregation at pH 6. Thus, our theoretical findings substantiate the possibility that Aβ oligomers develop intracellularly before secretion into the extracellular milieu, where they may disrupt synaptic activity or act as seeds for plaque formation.
β-turn | helix | pH-dependent | molecular dynamics | electrostatics
The authors declare no conflict of interest.
This article is a PNAS Direct Submission.
This article contains supporting information online at www.pnas.org/cgi/content/full/0703832104/DC1.
*To whom correspondence should be addressed. E-mail: brooks{at}scripps.edu
© 2007 by The National Academy of Sciences of the USA
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