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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...

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Autores principales: Nguyen, Hoang Linh, Linh, Huynh Quang, Matteini, Paolo, La Penna, Giovanni, Li, Mai Suan
Formato: Online Artículo Texto
Lenguaje:English
Publicado: American Chemical Society 2020
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.
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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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