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Emergence of Barrel Motif in Amyloid-β Trimer: A Computational Study
[Image: see text] Amyloid-β (Aβ) peptides form assemblies that are pathological hallmarks of Alzheimer’s disease. Aβ oligomers are soluble, mobile, and toxic forms of the peptide that act in the extracellular space before assembling into protofibrils and fibrils. Therefore, oligomers play an importa...
Autores principales: | , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
American Chemical
Society
2020
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Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7735726/ https://www.ncbi.nlm.nih.gov/pubmed/33180492 http://dx.doi.org/10.1021/acs.jpcb.0c05508 |
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author | Nguyen, Hoang Linh Linh, Huynh Quang Matteini, Paolo La Penna, Giovanni Li, Mai Suan |
author_facet | Nguyen, Hoang Linh Linh, Huynh Quang Matteini, Paolo La Penna, Giovanni Li, Mai Suan |
author_sort | Nguyen, Hoang Linh |
collection | PubMed |
description | [Image: see text] Amyloid-β (Aβ) peptides form assemblies that are pathological hallmarks of Alzheimer’s disease. Aβ oligomers are soluble, mobile, and toxic forms of the peptide that act in the extracellular space before assembling into protofibrils and fibrils. Therefore, oligomers play an important role in the mechanism of Alzheimer’s disease. Since it is difficult to determine by experiment the atomic structures of oligomers, which accumulate fast and are polymorphic, computer simulation is a useful tool to investigate elusive oligomers’ structures. In this work, we report extended all-atom molecular dynamics simulations, both canonical and replica exchange, of Aβ(1–42) trimer starting from two different initial conformations: (i) the pose produced by the best docking of a monomer aside of a dimer (simulation 1), representing oligomers freshly formed by assembling monomers, and (ii) a configuration extracted from an experimental mature fibril structure (simulation 2), representing settled oligomers in equilibrium with extended fibrils. We showed that in simulation 1, regions with small β-barrels are populated, indicating the chance of spontaneous formation of domains resembling channel-like structures. These structural domains are alternative to those more representative of mature fibrils (simulation 2), the latter showing a stable bundle of C-termini that is not sampled in simulation 1. Moreover, trimer of Aβ(1–42) can form internal pores that are large enough to be accessed by water molecules and Ca(2+) ions. |
format | Online Article Text |
id | pubmed-7735726 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2020 |
publisher | American Chemical
Society |
record_format | MEDLINE/PubMed |
spelling | pubmed-77357262020-12-15 Emergence of Barrel Motif in Amyloid-β Trimer: A Computational Study Nguyen, Hoang Linh Linh, Huynh Quang Matteini, Paolo La Penna, Giovanni Li, Mai Suan J Phys Chem B [Image: see text] Amyloid-β (Aβ) peptides form assemblies that are pathological hallmarks of Alzheimer’s disease. Aβ oligomers are soluble, mobile, and toxic forms of the peptide that act in the extracellular space before assembling into protofibrils and fibrils. Therefore, oligomers play an important role in the mechanism of Alzheimer’s disease. Since it is difficult to determine by experiment the atomic structures of oligomers, which accumulate fast and are polymorphic, computer simulation is a useful tool to investigate elusive oligomers’ structures. In this work, we report extended all-atom molecular dynamics simulations, both canonical and replica exchange, of Aβ(1–42) trimer starting from two different initial conformations: (i) the pose produced by the best docking of a monomer aside of a dimer (simulation 1), representing oligomers freshly formed by assembling monomers, and (ii) a configuration extracted from an experimental mature fibril structure (simulation 2), representing settled oligomers in equilibrium with extended fibrils. We showed that in simulation 1, regions with small β-barrels are populated, indicating the chance of spontaneous formation of domains resembling channel-like structures. These structural domains are alternative to those more representative of mature fibrils (simulation 2), the latter showing a stable bundle of C-termini that is not sampled in simulation 1. Moreover, trimer of Aβ(1–42) can form internal pores that are large enough to be accessed by water molecules and Ca(2+) ions. American Chemical Society 2020-11-12 2020-11-25 /pmc/articles/PMC7735726/ /pubmed/33180492 http://dx.doi.org/10.1021/acs.jpcb.0c05508 Text en © 2020 American Chemical Society This is an open access article published under a Creative Commons Attribution (CC-BY) License (http://pubs.acs.org/page/policy/authorchoice_ccby_termsofuse.html) , which permits unrestricted use, distribution and reproduction in any medium, provided the author and source are cited. |
spellingShingle | Nguyen, Hoang Linh Linh, Huynh Quang Matteini, Paolo La Penna, Giovanni Li, Mai Suan Emergence of Barrel Motif in Amyloid-β Trimer: A Computational Study |
title | Emergence of Barrel Motif in Amyloid-β
Trimer: A Computational Study |
title_full | Emergence of Barrel Motif in Amyloid-β
Trimer: A Computational Study |
title_fullStr | Emergence of Barrel Motif in Amyloid-β
Trimer: A Computational Study |
title_full_unstemmed | Emergence of Barrel Motif in Amyloid-β
Trimer: A Computational Study |
title_short | Emergence of Barrel Motif in Amyloid-β
Trimer: A Computational Study |
title_sort | emergence of barrel motif in amyloid-β
trimer: a computational study |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7735726/ https://www.ncbi.nlm.nih.gov/pubmed/33180492 http://dx.doi.org/10.1021/acs.jpcb.0c05508 |
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