Mapping the conformational dynamics and pathways of spontaneous steric zipper Peptide oligomerization.

The process of protein misfolding and self-assembly into various, polymorphic aggregates is associated with a number of important neurodegenerative diseases. Only recently, crystal structures of several short peptides have provided detailed structural insights into -sheet rich aggregates, known as a...

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Autores principales:	Dirk Matthes, Vytautas Gapsys, Venita Daebel, Bert L de Groot
Formato:	article
Lenguaje:	EN
Publicado:	Public Library of Science (PLoS) 2011
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/ab6fbce3cc9f4e6ca56fd3e71980b6c0
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spelling	oai:doaj.org-article:ab6fbce3cc9f4e6ca56fd3e71980b6c02021-11-18T06:54:34ZMapping the conformational dynamics and pathways of spontaneous steric zipper Peptide oligomerization.1932-620310.1371/journal.pone.0019129https://doaj.org/article/ab6fbce3cc9f4e6ca56fd3e71980b6c02011-05-01T00:00:00Zhttps://www.ncbi.nlm.nih.gov/pmc/articles/pmid/21559277/?tool=EBIhttps://doaj.org/toc/1932-6203The process of protein misfolding and self-assembly into various, polymorphic aggregates is associated with a number of important neurodegenerative diseases. Only recently, crystal structures of several short peptides have provided detailed structural insights into -sheet rich aggregates, known as amyloid fibrils. Knowledge about early events of the formation and interconversion of small oligomeric states, an inevitable step in the cascade of peptide self-assembly, however, remains still limited. We employ molecular dynamics simulations in explicit solvent to study the spontaneous aggregation process of steric zipper peptide segments from the tau protein and insulin in atomistic detail. Starting from separated chains with random conformations, we find a rapid formation of structurally heterogeneous, -sheet rich oligomers, emerging from multiple bimolecular association steps and diverse assembly pathways. Furthermore, our study provides evidence that aggregate intermediates as small as dimers can be kinetically trapped and thus affect the structural evolution of larger oligomers. Alternative aggregate structures are found for both peptide sequences in the different independent simulations, some of which feature characteristics of the known steric zipper conformation (e.g., -sheet bilayers with a dry interface). The final aggregates interconvert with topologically distinct oligomeric states exclusively via internal rearrangements. The peptide oligomerization was analyzed through the perspective of a minimal oligomer, i.e., the dimer. Thereby all observed multimeric aggregates can be consistently mapped onto a space of reduced dimensionality. This novel method of conformational mapping reveals heterogeneous association and reorganization dynamics that are governed by the characteristics of peptide sequence and oligomer size.Dirk MatthesVytautas GapsysVenita DaebelBert L de GrootPublic Library of Science (PLoS)articleMedicineRScienceQENPLoS ONE, Vol 6, Iss 5, p e19129 (2011)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Dirk Matthes Vytautas Gapsys Venita Daebel Bert L de Groot Mapping the conformational dynamics and pathways of spontaneous steric zipper Peptide oligomerization.
description	The process of protein misfolding and self-assembly into various, polymorphic aggregates is associated with a number of important neurodegenerative diseases. Only recently, crystal structures of several short peptides have provided detailed structural insights into -sheet rich aggregates, known as amyloid fibrils. Knowledge about early events of the formation and interconversion of small oligomeric states, an inevitable step in the cascade of peptide self-assembly, however, remains still limited. We employ molecular dynamics simulations in explicit solvent to study the spontaneous aggregation process of steric zipper peptide segments from the tau protein and insulin in atomistic detail. Starting from separated chains with random conformations, we find a rapid formation of structurally heterogeneous, -sheet rich oligomers, emerging from multiple bimolecular association steps and diverse assembly pathways. Furthermore, our study provides evidence that aggregate intermediates as small as dimers can be kinetically trapped and thus affect the structural evolution of larger oligomers. Alternative aggregate structures are found for both peptide sequences in the different independent simulations, some of which feature characteristics of the known steric zipper conformation (e.g., -sheet bilayers with a dry interface). The final aggregates interconvert with topologically distinct oligomeric states exclusively via internal rearrangements. The peptide oligomerization was analyzed through the perspective of a minimal oligomer, i.e., the dimer. Thereby all observed multimeric aggregates can be consistently mapped onto a space of reduced dimensionality. This novel method of conformational mapping reveals heterogeneous association and reorganization dynamics that are governed by the characteristics of peptide sequence and oligomer size.
format	article
author	Dirk Matthes Vytautas Gapsys Venita Daebel Bert L de Groot
author_facet	Dirk Matthes Vytautas Gapsys Venita Daebel Bert L de Groot
author_sort	Dirk Matthes
title	Mapping the conformational dynamics and pathways of spontaneous steric zipper Peptide oligomerization.
title_short	Mapping the conformational dynamics and pathways of spontaneous steric zipper Peptide oligomerization.
title_full	Mapping the conformational dynamics and pathways of spontaneous steric zipper Peptide oligomerization.
title_fullStr	Mapping the conformational dynamics and pathways of spontaneous steric zipper Peptide oligomerization.
title_full_unstemmed	Mapping the conformational dynamics and pathways of spontaneous steric zipper Peptide oligomerization.
title_sort	mapping the conformational dynamics and pathways of spontaneous steric zipper peptide oligomerization.
publisher	Public Library of Science (PLoS)
publishDate	2011
url	https://doaj.org/article/ab6fbce3cc9f4e6ca56fd3e71980b6c0
work_keys_str_mv	AT dirkmatthes mappingtheconformationaldynamicsandpathwaysofspontaneousstericzipperpeptideoligomerization AT vytautasgapsys mappingtheconformationaldynamicsandpathwaysofspontaneousstericzipperpeptideoligomerization AT venitadaebel mappingtheconformationaldynamicsandpathwaysofspontaneousstericzipperpeptideoligomerization AT bertldegroot mappingtheconformationaldynamicsandpathwaysofspontaneousstericzipperpeptideoligomerization
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Mapping the conformational dynamics and pathways of spontaneous steric zipper Peptide oligomerization.

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