Dynamics of metastable β-hairpin structures in the folding nucleus of amyloid β-protein

• Published in: The Journal of Physical Chemistry B
• Main Authors: Cruz, L, Rao, JS, Teplow, DB, Urbanc, B
• Format: Article in Journal/Newspaper
• Language: English
• Published: eScholarship, University of California 2012
• Subjects: Arctic
• Online Access: http://www.escholarship.org/uc/item/0jg6p377

The amyloid β-protein (Aβ), which is present predominately as a 40- or 42-residue peptide, is postulated to play a seminal role in the pathogenesis of Alzheimer's disease (AD). Folding of the Aβ21-30 decapeptide region is a critical step in the aggregation of Aβ. We report results of constant temperature all-atom molecular dynamics simulations in explicit water of the dynamics of monomeric Aβ21-30 and its Dutch [Glu22Gln], Arctic [Glu22Gly], and Iowa [Asp23Asn] isoforms that are associated with familial forms of cerebral amyloid angiopathy and AD. The simulations revealed a variety of loop conformers that exhibited a hydrogen bond network involving the Asp23 and Ser26 amino acids. A population of conformers, not part of the loop population, was found to form metastable β-hairpin structures with the highest probability in the Iowa mutant. At least three β-hairpin structures were found that differed in their hydrogen bonding register, average number of backbone hydrogen bonds, and lifetimes. Analysis revealed that the Dutch mutant had the longest β-hairpin lifetime (≥500 ns), closely followed by the Iowa mutant (≈500 ns). Aβ21-30 and the Arctic mutant had significantly lower lifetimes (≈200 ns). Hydrophobic packing of side chains was responsible for enhanced β-hairpin lifetimes in the Dutch and Iowa mutants, whereas lifetimes in Aβ21-30 and its Arctic mutant were influenced by the backbone hydrogen bonding. The data suggest that prolonged β-hairpin lifetimes may impact peptide pathogenicity in vivo. © 2012 American Chemical Society.