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Combined High-Pressure and Multiquantum NMR and Molecular Simulation Propose a Role for N-Terminal Salt Bridges in Amyloid-Beta
[Image: see text] Several lines of evidence point to the important role of the N-terminal region of amyloid-beta (Aβ) peptide in its toxic aggregation in Alzheimer’s disease (AD). It is known that charge-altering modifications such as Ser8 phosphorylation promote Aβ fibrillar aggregation. In this Le...
Autores principales: | , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
American Chemical Society
2021
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Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8521524/ https://www.ncbi.nlm.nih.gov/pubmed/34617758 http://dx.doi.org/10.1021/acs.jpclett.1c02595 |
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author | Vemulapalli, Sahithya Phani Babu Becker, Stefan Griesinger, Christian Rezaei-Ghaleh, Nasrollah |
author_facet | Vemulapalli, Sahithya Phani Babu Becker, Stefan Griesinger, Christian Rezaei-Ghaleh, Nasrollah |
author_sort | Vemulapalli, Sahithya Phani Babu |
collection | PubMed |
description | [Image: see text] Several lines of evidence point to the important role of the N-terminal region of amyloid-beta (Aβ) peptide in its toxic aggregation in Alzheimer’s disease (AD). It is known that charge-altering modifications such as Ser8 phosphorylation promote Aβ fibrillar aggregation. In this Letter, we combine high-pressure NMR, multiquantum chemical exchange saturation transfer (MQ-CEST) NMR, and microseconds-long molecular dynamics simulation and provide evidence of the presence of several salt bridges between Arg5 and its nearby negatively charged residues, in particular, Asp7 and Glu3. The presence of these salt bridges is correlated with less extended structures in the N-terminal region of Aβ. Through density functional theory calculations, we demonstrate how the introduction of negatively charged phosphoserine 8 influences the network of adjacent salt bridges in Aβ and favors more extended N-terminal structures. Our data propose a structural mechanism for the Ser8-phosphorylation-promoted Aβ aggregation and define the N-terminal salt bridges as potential targets for anti-AD drug design. |
format | Online Article Text |
id | pubmed-8521524 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2021 |
publisher | American Chemical Society |
record_format | MEDLINE/PubMed |
spelling | pubmed-85215242021-10-19 Combined High-Pressure and Multiquantum NMR and Molecular Simulation Propose a Role for N-Terminal Salt Bridges in Amyloid-Beta Vemulapalli, Sahithya Phani Babu Becker, Stefan Griesinger, Christian Rezaei-Ghaleh, Nasrollah J Phys Chem Lett [Image: see text] Several lines of evidence point to the important role of the N-terminal region of amyloid-beta (Aβ) peptide in its toxic aggregation in Alzheimer’s disease (AD). It is known that charge-altering modifications such as Ser8 phosphorylation promote Aβ fibrillar aggregation. In this Letter, we combine high-pressure NMR, multiquantum chemical exchange saturation transfer (MQ-CEST) NMR, and microseconds-long molecular dynamics simulation and provide evidence of the presence of several salt bridges between Arg5 and its nearby negatively charged residues, in particular, Asp7 and Glu3. The presence of these salt bridges is correlated with less extended structures in the N-terminal region of Aβ. Through density functional theory calculations, we demonstrate how the introduction of negatively charged phosphoserine 8 influences the network of adjacent salt bridges in Aβ and favors more extended N-terminal structures. Our data propose a structural mechanism for the Ser8-phosphorylation-promoted Aβ aggregation and define the N-terminal salt bridges as potential targets for anti-AD drug design. American Chemical Society 2021-10-07 2021-10-14 /pmc/articles/PMC8521524/ /pubmed/34617758 http://dx.doi.org/10.1021/acs.jpclett.1c02595 Text en © 2021 The Authors. Published by American Chemical Society https://creativecommons.org/licenses/by/4.0/Permits the broadest form of re-use including for commercial purposes, provided that author attribution and integrity are maintained (https://creativecommons.org/licenses/by/4.0/). |
spellingShingle | Vemulapalli, Sahithya Phani Babu Becker, Stefan Griesinger, Christian Rezaei-Ghaleh, Nasrollah Combined High-Pressure and Multiquantum NMR and Molecular Simulation Propose a Role for N-Terminal Salt Bridges in Amyloid-Beta |
title | Combined High-Pressure and Multiquantum NMR and Molecular
Simulation Propose a Role for N-Terminal Salt Bridges in Amyloid-Beta |
title_full | Combined High-Pressure and Multiquantum NMR and Molecular
Simulation Propose a Role for N-Terminal Salt Bridges in Amyloid-Beta |
title_fullStr | Combined High-Pressure and Multiquantum NMR and Molecular
Simulation Propose a Role for N-Terminal Salt Bridges in Amyloid-Beta |
title_full_unstemmed | Combined High-Pressure and Multiquantum NMR and Molecular
Simulation Propose a Role for N-Terminal Salt Bridges in Amyloid-Beta |
title_short | Combined High-Pressure and Multiquantum NMR and Molecular
Simulation Propose a Role for N-Terminal Salt Bridges in Amyloid-Beta |
title_sort | combined high-pressure and multiquantum nmr and molecular
simulation propose a role for n-terminal salt bridges in amyloid-beta |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8521524/ https://www.ncbi.nlm.nih.gov/pubmed/34617758 http://dx.doi.org/10.1021/acs.jpclett.1c02595 |
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