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...

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Autores principales:	Mookyung Cheon, Iksoo Chang, Sandipan Mohanty, Leila M Luheshi, Christopher M Dobson, Michele Vendruscolo, Giorgio Favrin
Formato:	article
Lenguaje:	EN
Publicado:	Public Library of Science (PLoS) 2007
Materias:	Biology (General) QH301-705.5
Acceso en línea:	https://doaj.org/article/26e62cab93244385a7f6815d4adeb4f9
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spelling	oai:doaj.org-article:26e62cab93244385a7f6815d4adeb4f92021-11-25T05:41:04ZStructural reorganisation and potential toxicity of oligomeric species formed during the assembly of amyloid fibrils.1553-734X1553-735810.1371/journal.pcbi.0030173https://doaj.org/article/26e62cab93244385a7f6815d4adeb4f92007-09-01T00:00:00Zhttps://doi.org/10.1371/journal.pcbi.0030173https://doaj.org/toc/1553-734Xhttps://doaj.org/toc/1553-7358Increasing 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 beta 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.Mookyung CheonIksoo ChangSandipan MohantyLeila M LuheshiChristopher M DobsonMichele VendruscoloGiorgio FavrinPublic Library of Science (PLoS)articleBiology (General)QH301-705.5ENPLoS Computational Biology, Vol 3, Iss 9, Pp 1727-1738 (2007)
institution	DOAJ
collection	DOAJ
language	EN
topic	Biology (General) QH301-705.5
spellingShingle	Biology (General) QH301-705.5 Mookyung Cheon Iksoo Chang Sandipan Mohanty Leila M Luheshi Christopher M Dobson Michele Vendruscolo Giorgio Favrin Structural reorganisation and potential toxicity of oligomeric species formed during the assembly of amyloid fibrils.
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 beta 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	article
author	Mookyung Cheon Iksoo Chang Sandipan Mohanty Leila M Luheshi Christopher M Dobson Michele Vendruscolo Giorgio Favrin
author_facet	Mookyung Cheon Iksoo Chang Sandipan Mohanty Leila M Luheshi Christopher M Dobson Michele Vendruscolo Giorgio Favrin
author_sort	Mookyung Cheon
title	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_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_sort	structural reorganisation and potential toxicity of oligomeric species formed during the assembly of amyloid fibrils.
publisher	Public Library of Science (PLoS)
publishDate	2007
url	https://doaj.org/article/26e62cab93244385a7f6815d4adeb4f9
work_keys_str_mv	AT mookyungcheon structuralreorganisationandpotentialtoxicityofoligomericspeciesformedduringtheassemblyofamyloidfibrils AT iksoochang structuralreorganisationandpotentialtoxicityofoligomericspeciesformedduringtheassemblyofamyloidfibrils AT sandipanmohanty structuralreorganisationandpotentialtoxicityofoligomericspeciesformedduringtheassemblyofamyloidfibrils AT leilamluheshi structuralreorganisationandpotentialtoxicityofoligomericspeciesformedduringtheassemblyofamyloidfibrils AT christophermdobson structuralreorganisationandpotentialtoxicityofoligomericspeciesformedduringtheassemblyofamyloidfibrils AT michelevendruscolo structuralreorganisationandpotentialtoxicityofoligomericspeciesformedduringtheassemblyofamyloidfibrils AT giorgiofavrin structuralreorganisationandpotentialtoxicityofoligomericspeciesformedduringtheassemblyofamyloidfibrils
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Structural reorganisation and potential toxicity of oligomeric species formed during the assembly of amyloid fibrils.

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