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Dynamics of metastable β-hairpin structures in the folding nucleus of amyloid β-protein
Journal article   Open access

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

L Cruz, J Srinivasa Rao, D B Teplow and B Urbanc
The journal of physical chemistry. B, v 116(22), pp 6311-6325
07 Jun 2012
DOI: https://doi.org/10.1021/jp301619v
PMID: 22587454
Featured in Collection :   UN Sustainable Development Goals @ Drexel
url
https://doi.org/10.1021/jp301619vView
Published, Version of Record (VoR) Open

Abstract

Protein Conformation Amyloid beta-Peptides - chemistry Molecular Dynamics Simulation Protein Folding
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 Aβ(21-30) 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 Aβ(21-30) 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). Aβ(21-30) 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 Aβ(21-30) 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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29 citations in Web of Science
29 citations in Scopus

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Collaboration types
Domestic collaboration
Web of Science research areas
Biophysics
Chemistry, Physical
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