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Structural Reorganisation and Potential Toxicity of Oligomeric Species Formed during the Assembly of Amyloid Fibrils
Increasing evidence indicates that oligomeric protein assemblies may represent the molecular species responsible for cytotoxicity in a range of neurological disorders including Alzheimer and Parkinson diseases. We use all-atom computer simulations to reveal that the process of oligomerization can be...
Autores principales: | , , , , , , |
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Formato: | Texto |
Lenguaje: | English |
Publicado: |
Public Library of Science
2007
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1976335/ https://www.ncbi.nlm.nih.gov/pubmed/17941703 http://dx.doi.org/10.1371/journal.pcbi.0030173 |
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author | Cheon, Mookyung Chang, Iksoo Mohanty, Sandipan Luheshi, Leila M Dobson, Christopher M Vendruscolo, Michele Favrin, Giorgio |
author_facet | Cheon, Mookyung Chang, Iksoo Mohanty, Sandipan Luheshi, Leila M Dobson, Christopher M Vendruscolo, Michele Favrin, Giorgio |
author_sort | Cheon, Mookyung |
collection | PubMed |
description | Increasing evidence indicates that oligomeric protein assemblies may represent the molecular species responsible for cytotoxicity in a range of neurological disorders including Alzheimer and Parkinson diseases. We use all-atom computer simulations to reveal that the process of oligomerization can be divided into two steps. The first is characterised by a hydrophobic coalescence resulting in the formation of molten oligomers in which hydrophobic residues are sequestered away from the solvent. In the second step, the oligomers undergo a process of reorganisation driven by interchain hydrogen bonding interactions that induce the formation of β sheet rich assemblies in which hydrophobic groups can become exposed. Our results show that the process of aggregation into either ordered or amorphous species is largely determined by a competition between the hydrophobicity of the amino acid sequence and the tendency of polypeptide chains to form arrays of hydrogen bonds. We discuss how the increase in solvent-exposed hydrophobic surface resulting from such a competition offers an explanation for recent observations concerning the cytotoxicity of oligomeric species formed prior to mature amyloid fibrils. |
format | Text |
id | pubmed-1976335 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2007 |
publisher | Public Library of Science |
record_format | MEDLINE/PubMed |
spelling | pubmed-19763352007-09-28 Structural Reorganisation and Potential Toxicity of Oligomeric Species Formed during the Assembly of Amyloid Fibrils Cheon, Mookyung Chang, Iksoo Mohanty, Sandipan Luheshi, Leila M Dobson, Christopher M Vendruscolo, Michele Favrin, Giorgio PLoS Comput Biol Research Article Increasing evidence indicates that oligomeric protein assemblies may represent the molecular species responsible for cytotoxicity in a range of neurological disorders including Alzheimer and Parkinson diseases. We use all-atom computer simulations to reveal that the process of oligomerization can be divided into two steps. The first is characterised by a hydrophobic coalescence resulting in the formation of molten oligomers in which hydrophobic residues are sequestered away from the solvent. In the second step, the oligomers undergo a process of reorganisation driven by interchain hydrogen bonding interactions that induce the formation of β sheet rich assemblies in which hydrophobic groups can become exposed. Our results show that the process of aggregation into either ordered or amorphous species is largely determined by a competition between the hydrophobicity of the amino acid sequence and the tendency of polypeptide chains to form arrays of hydrogen bonds. We discuss how the increase in solvent-exposed hydrophobic surface resulting from such a competition offers an explanation for recent observations concerning the cytotoxicity of oligomeric species formed prior to mature amyloid fibrils. Public Library of Science 2007-09 2007-09-14 /pmc/articles/PMC1976335/ /pubmed/17941703 http://dx.doi.org/10.1371/journal.pcbi.0030173 Text en © 2007 Cheon et al. http://creativecommons.org/licenses/by/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are properly credited. |
spellingShingle | Research Article Cheon, Mookyung Chang, Iksoo Mohanty, Sandipan Luheshi, Leila M Dobson, Christopher M Vendruscolo, Michele Favrin, Giorgio Structural Reorganisation and Potential Toxicity of Oligomeric Species Formed during the Assembly of Amyloid Fibrils |
title | Structural Reorganisation and Potential Toxicity of Oligomeric Species Formed during the Assembly of Amyloid Fibrils |
title_full | Structural Reorganisation and Potential Toxicity of Oligomeric Species Formed during the Assembly of Amyloid Fibrils |
title_fullStr | Structural Reorganisation and Potential Toxicity of Oligomeric Species Formed during the Assembly of Amyloid Fibrils |
title_full_unstemmed | Structural Reorganisation and Potential Toxicity of Oligomeric Species Formed during the Assembly of Amyloid Fibrils |
title_short | Structural Reorganisation and Potential Toxicity of Oligomeric Species Formed during the Assembly of Amyloid Fibrils |
title_sort | structural reorganisation and potential toxicity of oligomeric species formed during the assembly of amyloid fibrils |
topic | Research Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1976335/ https://www.ncbi.nlm.nih.gov/pubmed/17941703 http://dx.doi.org/10.1371/journal.pcbi.0030173 |
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