Exploring the early stages of chemical unfolding of proteins at the proteome scale

After decades of using urea as denaturant, the kinetic role of this molecule in the unfolding process is still undefined: does urea actively induce protein unfolding or passively stabilize the unfolded state? By analyzing a set of 30 proteins (representative of all native folds) through extensive mo...

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Autores: Candotti, Michela, Pérez, Alberto, Ferrer Costa, Carles, Rueda Borrego, Manuel, Meyer, Tim, Gelpí Buchaca, Josep Lluís, Orozco López, Modesto
Tipo de recurso: artículo
Estado:Versión publicada
Fecha de publicación:2013
País:España
Institución:Varias* (Consorci de Biblioteques Universitáries de Catalunya, Centre de Serveis Científics i Acadèmics de Catalunya)
Repositorio:Recercat. Dipósit de la Recerca de Catalunya
OAI Identifier:oai:recercat.cat:2445/147783
Acceso en línea:https://hdl.handle.net/2445/147783
Access Level:acceso abierto
Palabra clave:Desnaturalització de proteïnes
Urea
Protein denaturation
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spelling Exploring the early stages of chemical unfolding of proteins at the proteome scaleCandotti, MichelaPérez, AlbertoFerrer Costa, CarlesRueda Borrego, ManuelMeyer, TimGelpí Buchaca, Josep LluísOrozco López, ModestoDesnaturalització de proteïnesUreaProtein denaturationUreaAfter decades of using urea as denaturant, the kinetic role of this molecule in the unfolding process is still undefined: does urea actively induce protein unfolding or passively stabilize the unfolded state? By analyzing a set of 30 proteins (representative of all native folds) through extensive molecular dynamics simulations in denaturant (using a range of force-fields), we derived robust rules for urea unfolding that are valid at the proteome level. Irrespective of the protein fold, presence or absence of disulphide bridges, and secondary structure composition, urea concentrates in the first solvation shell of quasi-native proteins, but with a density lower than that of the fully unfolded state. The presence of urea does not alter the spontaneous vibration pattern of proteins. In fact, it reduces the magnitude of such vibrations, leading to a counterintuitive slow down of the atomic-motions that opposes unfolding. Urea stickiness and slow diffusion is, however, crucial for unfolding. Long residence urea molecules placed around the hydrophobic core are crucial to stabilize partially open structures generated by thermal fluctuations. Our simulations indicate that although urea does not favor the formation of partially open microstates, it is not a mere spectator of unfolding that simply displaces to the right of the folded←→unfolded equilibrium. On the contrary, urea actively favors unfolding: it selects and stabilizes partially unfolded microstates, slowly driving the protein conformational ensemble far from the native one and also from the conformations sampled during thermal unfolding.Public Library of Science (PLoS)2020202020132020info:eu-repo/semantics/articleinfo:eu-repo/semantics/publishedVersion11 p.application/pdfhttps://hdl.handle.net/2445/147783Articles publicats en revistes (Bioquímica i Biomedicina Molecular)reponame:Recercat. Dipósit de la Recerca de Catalunyainstname:Varias* (Consorci de Biblioteques Universitáries de Catalunya, Centre de Serveis Científics i Acadèmics de Catalunya)InglésReproducció del document publicat a: https://doi.org/10.1371/journal.pcbi.1003393PLoS Computational Biology, 2013, vol. 9, num. 12, p. e1003393https://doi.org/10.1371/journal.pcbi.1003393info:eu-repo/grantAgreement/EC/FP7/291433cc-by (c) Candotti, Michela et al., 2013http://creativecommons.org/licenses/by/3.0/esinfo:eu-repo/semantics/openAccessoai:recercat.cat:2445/1477832026-05-29T05:05:01Z
dc.title.none.fl_str_mv Exploring the early stages of chemical unfolding of proteins at the proteome scale
title Exploring the early stages of chemical unfolding of proteins at the proteome scale
spellingShingle Exploring the early stages of chemical unfolding of proteins at the proteome scale
Candotti, Michela
Desnaturalització de proteïnes
Urea
Protein denaturation
Urea
title_short Exploring the early stages of chemical unfolding of proteins at the proteome scale
title_full Exploring the early stages of chemical unfolding of proteins at the proteome scale
title_fullStr Exploring the early stages of chemical unfolding of proteins at the proteome scale
title_full_unstemmed Exploring the early stages of chemical unfolding of proteins at the proteome scale
title_sort Exploring the early stages of chemical unfolding of proteins at the proteome scale
dc.creator.none.fl_str_mv Candotti, Michela
Pérez, Alberto
Ferrer Costa, Carles
Rueda Borrego, Manuel
Meyer, Tim
Gelpí Buchaca, Josep Lluís
Orozco López, Modesto
author Candotti, Michela
author_facet Candotti, Michela
Pérez, Alberto
Ferrer Costa, Carles
Rueda Borrego, Manuel
Meyer, Tim
Gelpí Buchaca, Josep Lluís
Orozco López, Modesto
author_role author
author2 Pérez, Alberto
Ferrer Costa, Carles
Rueda Borrego, Manuel
Meyer, Tim
Gelpí Buchaca, Josep Lluís
Orozco López, Modesto
author2_role author
author
author
author
author
author
dc.subject.none.fl_str_mv Desnaturalització de proteïnes
Urea
Protein denaturation
Urea
topic Desnaturalització de proteïnes
Urea
Protein denaturation
Urea
description After decades of using urea as denaturant, the kinetic role of this molecule in the unfolding process is still undefined: does urea actively induce protein unfolding or passively stabilize the unfolded state? By analyzing a set of 30 proteins (representative of all native folds) through extensive molecular dynamics simulations in denaturant (using a range of force-fields), we derived robust rules for urea unfolding that are valid at the proteome level. Irrespective of the protein fold, presence or absence of disulphide bridges, and secondary structure composition, urea concentrates in the first solvation shell of quasi-native proteins, but with a density lower than that of the fully unfolded state. The presence of urea does not alter the spontaneous vibration pattern of proteins. In fact, it reduces the magnitude of such vibrations, leading to a counterintuitive slow down of the atomic-motions that opposes unfolding. Urea stickiness and slow diffusion is, however, crucial for unfolding. Long residence urea molecules placed around the hydrophobic core are crucial to stabilize partially open structures generated by thermal fluctuations. Our simulations indicate that although urea does not favor the formation of partially open microstates, it is not a mere spectator of unfolding that simply displaces to the right of the folded←→unfolded equilibrium. On the contrary, urea actively favors unfolding: it selects and stabilizes partially unfolded microstates, slowly driving the protein conformational ensemble far from the native one and also from the conformations sampled during thermal unfolding.
publishDate 2013
dc.date.none.fl_str_mv 2013
2020
2020
2020
dc.type.none.fl_str_mv info:eu-repo/semantics/article
info:eu-repo/semantics/publishedVersion
format article
status_str publishedVersion
dc.identifier.none.fl_str_mv https://hdl.handle.net/2445/147783
url https://hdl.handle.net/2445/147783
dc.language.none.fl_str_mv Inglés
language_invalid_str_mv Inglés
dc.relation.none.fl_str_mv Reproducció del document publicat a: https://doi.org/10.1371/journal.pcbi.1003393
PLoS Computational Biology, 2013, vol. 9, num. 12, p. e1003393
https://doi.org/10.1371/journal.pcbi.1003393
info:eu-repo/grantAgreement/EC/FP7/291433
dc.rights.none.fl_str_mv cc-by (c) Candotti, Michela et al., 2013
http://creativecommons.org/licenses/by/3.0/es
info:eu-repo/semantics/openAccess
rights_invalid_str_mv cc-by (c) Candotti, Michela et al., 2013
http://creativecommons.org/licenses/by/3.0/es
eu_rights_str_mv openAccess
dc.format.none.fl_str_mv 11 p.
application/pdf
dc.publisher.none.fl_str_mv Public Library of Science (PLoS)
publisher.none.fl_str_mv Public Library of Science (PLoS)
dc.source.none.fl_str_mv Articles publicats en revistes (Bioquímica i Biomedicina Molecular)
reponame:Recercat. Dipósit de la Recerca de Catalunya
instname:Varias* (Consorci de Biblioteques Universitáries de Catalunya, Centre de Serveis Científics i Acadèmics de Catalunya)
instname_str Varias* (Consorci de Biblioteques Universitáries de Catalunya, Centre de Serveis Científics i Acadèmics de Catalunya)
reponame_str Recercat. Dipósit de la Recerca de Catalunya
collection Recercat. Dipósit de la Recerca de Catalunya
repository.name.fl_str_mv
repository.mail.fl_str_mv
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score 15.812429

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