Dynamics of Metastable β-hairpin Structures in the Folding Nucleus of Amyloid β-Protein
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 t...
Published in: | The Journal of Physical Chemistry B |
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Main Authors: | , , , |
Format: | Text |
Language: | English |
Published: |
2012
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Subjects: | |
Online Access: | http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3394227 http://www.ncbi.nlm.nih.gov/pubmed/22587454 https://doi.org/10.1021/jp301619v |
Summary: | 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 (≥500ns), closely followed by the Iowa mutant (≈500ns). Aβ21–30 and the Arctic mutant had significantly lower lifetimes (≈200ns). 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. |
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