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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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 |
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ftpubmed:oai:pubmedcentral.nih.gov:3394227 2023-05-15T14:54:21+02:00 Dynamics of Metastable β-hairpin Structures in the Folding Nucleus of Amyloid β-Protein Cruz, L Srinivasa Rao, J Teplow, D. B. Urbanc, B 2012-05-24 http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3394227 http://www.ncbi.nlm.nih.gov/pubmed/22587454 https://doi.org/10.1021/jp301619v en eng http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3394227 http://www.ncbi.nlm.nih.gov/pubmed/22587454 http://dx.doi.org/10.1021/jp301619v Article Text 2012 ftpubmed https://doi.org/10.1021/jp301619v 2013-09-04T09:56:48Z 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. Text Arctic PubMed Central (PMC) Arctic The Journal of Physical Chemistry B 116 22 6311 6325 |
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Article Cruz, L Srinivasa Rao, J Teplow, D. B. Urbanc, B Dynamics of Metastable β-hairpin Structures in the Folding Nucleus of Amyloid β-Protein |
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description |
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. |
format |
Text |
author |
Cruz, L Srinivasa Rao, J Teplow, D. B. Urbanc, B |
author_facet |
Cruz, L Srinivasa Rao, J Teplow, D. B. Urbanc, B |
author_sort |
Cruz, L |
title |
Dynamics of Metastable β-hairpin Structures in the Folding Nucleus of Amyloid β-Protein |
title_short |
Dynamics of Metastable β-hairpin Structures in the Folding Nucleus of Amyloid β-Protein |
title_full |
Dynamics of Metastable β-hairpin Structures in the Folding Nucleus of Amyloid β-Protein |
title_fullStr |
Dynamics of Metastable β-hairpin Structures in the Folding Nucleus of Amyloid β-Protein |
title_full_unstemmed |
Dynamics of Metastable β-hairpin Structures in the Folding Nucleus of Amyloid β-Protein |
title_sort |
dynamics of metastable β-hairpin structures in the folding nucleus of amyloid β-protein |
publishDate |
2012 |
url |
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3394227 http://www.ncbi.nlm.nih.gov/pubmed/22587454 https://doi.org/10.1021/jp301619v |
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3394227 http://www.ncbi.nlm.nih.gov/pubmed/22587454 http://dx.doi.org/10.1021/jp301619v |
op_doi |
https://doi.org/10.1021/jp301619v |
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The Journal of Physical Chemistry B |
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116 |
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22 |
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6311 |
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6325 |
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1766326062325694464 |