Polymorphism at 129 dictates metastable conformations of the human prion protein N-terminal β-sheet

Autores
Paz, Sergio Alexis; Vanden-Eijnden, Eric; Abrams, Cameron F.
Año de publicación
2017
Idioma
inglés
Tipo de recurso
artículo
Estado
versión publicada
Descripción
We study the thermodynamic stability of the native state of the human prion protein using a new free-energy method, replica-exchange on-the-fly parameterization. This method is designed to overcome hidden-variable sampling limitations to yield nearly error-free free-energy profiles along a conformational coordinate. We confirm that all four (M129V, D178N) polymorphs have a ground-state conformation with three intact β-sheet hydrogen bonds. Additionally, they are observed to have distinct metastabilities determined by the side-chain at position 129. We rationalize these findings with reference to the prion “strain” hypothesis, which links the variety of transmissible spongiform encephalopathy phenotypes to conformationally distinct infectious prion forms and classifies distinct phenotypes of sporadic Creutzfeldt-Jakob disease based solely on the 129 polymorphism. Because such metastable structures are not easily observed in structural experiments, our approach could potentially provide new insights into the conformational origins of prion diseases and other pathologies arising from protein misfolding and aggregation.
Fil: Paz, Sergio Alexis. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Drexel University; Estados Unidos
Fil: Vanden-Eijnden, Eric. University of New York; Estados Unidos
Fil: Abrams, Cameron F.. Drexel University; Estados Unidos
Materia
FREE ENERGY
PRION PROTEIN
REPLICA EXCHANGE
OTFP
Nivel de accesibilidad
acceso abierto
Condiciones de uso
https://creativecommons.org/licenses/by-nc-sa/2.5/ar/
Repositorio
CONICET Digital (CONICET)
Institución
Consejo Nacional de Investigaciones Científicas y Técnicas
OAI Identificador
oai:ri.conicet.gov.ar:11336/62313
Acceder
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oai_identifier_str oai:ri.conicet.gov.ar:11336/62313
network_acronym_str CONICETDig
repository_id_str 3498
network_name_str CONICET Digital (CONICET)
spelling Polymorphism at 129 dictates metastable conformations of the human prion protein N-terminal β-sheetPaz, Sergio AlexisVanden-Eijnden, EricAbrams, Cameron F.FREE ENERGYPRION PROTEINREPLICA EXCHANGEOTFPhttps://purl.org/becyt/ford/1.4https://purl.org/becyt/ford/1We study the thermodynamic stability of the native state of the human prion protein using a new free-energy method, replica-exchange on-the-fly parameterization. This method is designed to overcome hidden-variable sampling limitations to yield nearly error-free free-energy profiles along a conformational coordinate. We confirm that all four (M129V, D178N) polymorphs have a ground-state conformation with three intact β-sheet hydrogen bonds. Additionally, they are observed to have distinct metastabilities determined by the side-chain at position 129. We rationalize these findings with reference to the prion “strain” hypothesis, which links the variety of transmissible spongiform encephalopathy phenotypes to conformationally distinct infectious prion forms and classifies distinct phenotypes of sporadic Creutzfeldt-Jakob disease based solely on the 129 polymorphism. Because such metastable structures are not easily observed in structural experiments, our approach could potentially provide new insights into the conformational origins of prion diseases and other pathologies arising from protein misfolding and aggregation.Fil: Paz, Sergio Alexis. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Drexel University; Estados UnidosFil: Vanden-Eijnden, Eric. University of New York; Estados UnidosFil: Abrams, Cameron F.. Drexel University; Estados UnidosRoyal Society of Chemistry2017-08-30info:eu-repo/semantics/articleinfo:eu-repo/semantics/publishedVersionhttp://purl.org/coar/resource_type/c_6501info:ar-repo/semantics/articuloapplication/pdfapplication/pdfhttp://hdl.handle.net/11336/62313Paz, Sergio Alexis; Vanden-Eijnden, Eric; Abrams, Cameron F.; Polymorphism at 129 dictates metastable conformations of the human prion protein N-terminal β-sheet; Royal Society of Chemistry; Chemical Science; 8; 2; 30-8-2017; 1225-12322041-65202041-6539CONICET DigitalCONICETenginfo:eu-repo/semantics/altIdentifier/url/https://pubs.rsc.org/en/Content/ArticleLanding/2017/SC/C6SC03275Cinfo:eu-repo/semantics/altIdentifier/doi/10.1039/C6SC03275Cinfo:eu-repo/semantics/openAccesshttps://creativecommons.org/licenses/by-nc-sa/2.5/ar/reponame:CONICET Digital (CONICET)instname:Consejo Nacional de Investigaciones Científicas y Técnicas2025-10-22T11:03:12Zoai:ri.conicet.gov.ar:11336/62313instacron:CONICETInstitucionalhttp://ri.conicet.gov.ar/Organismo científico-tecnológicoNo correspondehttp://ri.conicet.gov.ar/oai/requestdasensio@conicet.gov.ar; lcarlino@conicet.gov.arArgentinaNo correspondeNo correspondeNo correspondeopendoar:34982025-10-22 11:03:12.88CONICET Digital (CONICET) - Consejo Nacional de Investigaciones Científicas y Técnicasfalse
dc.title.none.fl_str_mv Polymorphism at 129 dictates metastable conformations of the human prion protein N-terminal β-sheet
title Polymorphism at 129 dictates metastable conformations of the human prion protein N-terminal β-sheet
spellingShingle Polymorphism at 129 dictates metastable conformations of the human prion protein N-terminal β-sheet
Paz, Sergio Alexis
FREE ENERGY
PRION PROTEIN
REPLICA EXCHANGE
OTFP
title_short Polymorphism at 129 dictates metastable conformations of the human prion protein N-terminal β-sheet
title_full Polymorphism at 129 dictates metastable conformations of the human prion protein N-terminal β-sheet
title_fullStr Polymorphism at 129 dictates metastable conformations of the human prion protein N-terminal β-sheet
title_full_unstemmed Polymorphism at 129 dictates metastable conformations of the human prion protein N-terminal β-sheet
title_sort Polymorphism at 129 dictates metastable conformations of the human prion protein N-terminal β-sheet
dc.creator.none.fl_str_mv Paz, Sergio Alexis
Vanden-Eijnden, Eric
Abrams, Cameron F.
author Paz, Sergio Alexis
author_facet Paz, Sergio Alexis
Vanden-Eijnden, Eric
Abrams, Cameron F.
author_role author
author2 Vanden-Eijnden, Eric
Abrams, Cameron F.
author2_role author
author
dc.subject.none.fl_str_mv FREE ENERGY
PRION PROTEIN
REPLICA EXCHANGE
OTFP
topic FREE ENERGY
PRION PROTEIN
REPLICA EXCHANGE
OTFP
purl_subject.fl_str_mv https://purl.org/becyt/ford/1.4
https://purl.org/becyt/ford/1
dc.description.none.fl_txt_mv We study the thermodynamic stability of the native state of the human prion protein using a new free-energy method, replica-exchange on-the-fly parameterization. This method is designed to overcome hidden-variable sampling limitations to yield nearly error-free free-energy profiles along a conformational coordinate. We confirm that all four (M129V, D178N) polymorphs have a ground-state conformation with three intact β-sheet hydrogen bonds. Additionally, they are observed to have distinct metastabilities determined by the side-chain at position 129. We rationalize these findings with reference to the prion “strain” hypothesis, which links the variety of transmissible spongiform encephalopathy phenotypes to conformationally distinct infectious prion forms and classifies distinct phenotypes of sporadic Creutzfeldt-Jakob disease based solely on the 129 polymorphism. Because such metastable structures are not easily observed in structural experiments, our approach could potentially provide new insights into the conformational origins of prion diseases and other pathologies arising from protein misfolding and aggregation.
Fil: Paz, Sergio Alexis. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Drexel University; Estados Unidos
Fil: Vanden-Eijnden, Eric. University of New York; Estados Unidos
Fil: Abrams, Cameron F.. Drexel University; Estados Unidos
description We study the thermodynamic stability of the native state of the human prion protein using a new free-energy method, replica-exchange on-the-fly parameterization. This method is designed to overcome hidden-variable sampling limitations to yield nearly error-free free-energy profiles along a conformational coordinate. We confirm that all four (M129V, D178N) polymorphs have a ground-state conformation with three intact β-sheet hydrogen bonds. Additionally, they are observed to have distinct metastabilities determined by the side-chain at position 129. We rationalize these findings with reference to the prion “strain” hypothesis, which links the variety of transmissible spongiform encephalopathy phenotypes to conformationally distinct infectious prion forms and classifies distinct phenotypes of sporadic Creutzfeldt-Jakob disease based solely on the 129 polymorphism. Because such metastable structures are not easily observed in structural experiments, our approach could potentially provide new insights into the conformational origins of prion diseases and other pathologies arising from protein misfolding and aggregation.
publishDate 2017
dc.date.none.fl_str_mv 2017-08-30
dc.type.none.fl_str_mv info:eu-repo/semantics/article
info:eu-repo/semantics/publishedVersion
http://purl.org/coar/resource_type/c_6501
info:ar-repo/semantics/articulo
format article
status_str publishedVersion
dc.identifier.none.fl_str_mv http://hdl.handle.net/11336/62313
Paz, Sergio Alexis; Vanden-Eijnden, Eric; Abrams, Cameron F.; Polymorphism at 129 dictates metastable conformations of the human prion protein N-terminal β-sheet; Royal Society of Chemistry; Chemical Science; 8; 2; 30-8-2017; 1225-1232
2041-6520
2041-6539
CONICET Digital
CONICET
url http://hdl.handle.net/11336/62313
identifier_str_mv Paz, Sergio Alexis; Vanden-Eijnden, Eric; Abrams, Cameron F.; Polymorphism at 129 dictates metastable conformations of the human prion protein N-terminal β-sheet; Royal Society of Chemistry; Chemical Science; 8; 2; 30-8-2017; 1225-1232
2041-6520
2041-6539
CONICET Digital
CONICET
dc.language.none.fl_str_mv eng
language eng
dc.relation.none.fl_str_mv info:eu-repo/semantics/altIdentifier/url/https://pubs.rsc.org/en/Content/ArticleLanding/2017/SC/C6SC03275C
info:eu-repo/semantics/altIdentifier/doi/10.1039/C6SC03275C
dc.rights.none.fl_str_mv info:eu-repo/semantics/openAccess
https://creativecommons.org/licenses/by-nc-sa/2.5/ar/
eu_rights_str_mv openAccess
rights_invalid_str_mv https://creativecommons.org/licenses/by-nc-sa/2.5/ar/
dc.format.none.fl_str_mv application/pdf
application/pdf
dc.publisher.none.fl_str_mv Royal Society of Chemistry
publisher.none.fl_str_mv Royal Society of Chemistry
dc.source.none.fl_str_mv reponame:CONICET Digital (CONICET)
instname:Consejo Nacional de Investigaciones Científicas y Técnicas
reponame_str CONICET Digital (CONICET)
collection CONICET Digital (CONICET)
instname_str Consejo Nacional de Investigaciones Científicas y Técnicas
repository.name.fl_str_mv CONICET Digital (CONICET) - Consejo Nacional de Investigaciones Científicas y Técnicas
repository.mail.fl_str_mv dasensio@conicet.gov.ar; lcarlino@conicet.gov.ar
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score 12.982451

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