On the effect of protein conformation diversity in discriminating among neutral and disease related single amino acid substitutions

Autores
Juritz, Ezequiel; Fornasari, Maria Silvina; Martelli, Pier Luigi; Fariselli, Piero; Casadio, Rita; Parisi, Gustavo Daniel
Año de publicación
2012
Idioma
inglés
Tipo de recurso
artículo
Estado
versión publicada
Descripción
Background: Non-synonymous coding SNPs (nsSNPs) that are associated to disease can also be related with alterations in protein stability. Computational methods are available to predict the effect of single amino acid substitutions (SASs) on protein stability based on a single folded structure. However, the native state of a protein is not unique and it is better represented by the ensemble of its conformers in dynamic equilibrium. The maintenance of the ensemble is essential for protein function. In this work we investigated how protein conformational diversity can affect the discrimination of neutral and disease related SASs based on protein stability estimations. For this purpose, we used 119 proteins with 803 associated SASs, 60% of which are disease related. Each protein was associated with its corresponding set of available conformers as found in the Protein Conformational Database (PCDB). Our dataset contains proteins with different extensions of conformational diversity summing up a total number of 1023 conformers. Results: The existence of different conformers for a given protein introduces great variability in the estimation of the protein stability (ΔΔG) after a single amino acid substitution (SAS) as computed with FoldX. Indeed, in 35% of our protein set at least one SAS can be described as stabilizing, destabilizing or neutral when a cutoff value of ±2 kcal/mol is adopted for discriminating neutral from perturbing SASs. However, when the ΔΔG variability among conformers is taken into account, the correlation among the perturbation of protein stability and the corresponding disease or neutral phenotype increases as compared with the same analysis on single protein structures. At the conformer level, we also found that the different conformers correlate in a different way to the corresponding phenotype. Conclusions: Our results suggest that the consideration of conformational diversity can improve the discrimination of neutral and disease related protein SASs based on the evaluation of the corresponding Gibbs free energy change.
Fil: Juritz, Ezequiel. Universidad Nacional de Quilmes. Departamento de Ciencia y Tecnología; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina
Fil: Fornasari, Maria Silvina. Universidad Nacional de Quilmes. Departamento de Ciencia y Tecnología; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina
Fil: Martelli, Pier Luigi. No especifíca;
Fil: Fariselli, Piero. No especifíca;
Fil: Casadio, Rita. No especifíca;
Fil: Parisi, Gustavo Daniel. Universidad Nacional de Quilmes. Departamento de Ciencia y Tecnología; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina
Materia
Mutations
Protein stability
Neutral substitutions
Protein conformational diversity
Nivel de accesibilidad
acceso abierto
Condiciones de uso
https://creativecommons.org/licenses/by/2.5/ar/
Repositorio
CONICET Digital (CONICET)
Institución
Consejo Nacional de Investigaciones Científicas y Técnicas
OAI Identificador
oai:ri.conicet.gov.ar:11336/273442
Acceder
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oai_identifier_str oai:ri.conicet.gov.ar:11336/273442
network_acronym_str CONICETDig
repository_id_str 3498
network_name_str CONICET Digital (CONICET)
spelling On the effect of protein conformation diversity in discriminating among neutral and disease related single amino acid substitutionsJuritz, EzequielFornasari, Maria SilvinaMartelli, Pier LuigiFariselli, PieroCasadio, RitaParisi, Gustavo DanielMutationsProtein stabilityNeutral substitutionsProtein conformational diversityhttps://purl.org/becyt/ford/1.6https://purl.org/becyt/ford/1Background: Non-synonymous coding SNPs (nsSNPs) that are associated to disease can also be related with alterations in protein stability. Computational methods are available to predict the effect of single amino acid substitutions (SASs) on protein stability based on a single folded structure. However, the native state of a protein is not unique and it is better represented by the ensemble of its conformers in dynamic equilibrium. The maintenance of the ensemble is essential for protein function. In this work we investigated how protein conformational diversity can affect the discrimination of neutral and disease related SASs based on protein stability estimations. For this purpose, we used 119 proteins with 803 associated SASs, 60% of which are disease related. Each protein was associated with its corresponding set of available conformers as found in the Protein Conformational Database (PCDB). Our dataset contains proteins with different extensions of conformational diversity summing up a total number of 1023 conformers. Results: The existence of different conformers for a given protein introduces great variability in the estimation of the protein stability (ΔΔG) after a single amino acid substitution (SAS) as computed with FoldX. Indeed, in 35% of our protein set at least one SAS can be described as stabilizing, destabilizing or neutral when a cutoff value of ±2 kcal/mol is adopted for discriminating neutral from perturbing SASs. However, when the ΔΔG variability among conformers is taken into account, the correlation among the perturbation of protein stability and the corresponding disease or neutral phenotype increases as compared with the same analysis on single protein structures. At the conformer level, we also found that the different conformers correlate in a different way to the corresponding phenotype. Conclusions: Our results suggest that the consideration of conformational diversity can improve the discrimination of neutral and disease related protein SASs based on the evaluation of the corresponding Gibbs free energy change.Fil: Juritz, Ezequiel. Universidad Nacional de Quilmes. Departamento de Ciencia y Tecnología; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; ArgentinaFil: Fornasari, Maria Silvina. Universidad Nacional de Quilmes. Departamento de Ciencia y Tecnología; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; ArgentinaFil: Martelli, Pier Luigi. No especifíca;Fil: Fariselli, Piero. No especifíca;Fil: Casadio, Rita. No especifíca;Fil: Parisi, Gustavo Daniel. Universidad Nacional de Quilmes. Departamento de Ciencia y Tecnología; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; ArgentinaBioMed Central2012-06info:eu-repo/semantics/articleinfo:eu-repo/semantics/publishedVersionhttp://purl.org/coar/resource_type/c_6501info:ar-repo/semantics/articuloapplication/pdfapplication/pdfapplication/pdfhttp://hdl.handle.net/11336/273442Juritz, Ezequiel; Fornasari, Maria Silvina; Martelli, Pier Luigi; Fariselli, Piero; Casadio, Rita; et al.; On the effect of protein conformation diversity in discriminating among neutral and disease related single amino acid substitutions; BioMed Central; BMC Genomics; 13; S5; 6-2012; 1-91471-2164CONICET DigitalCONICETenginfo:eu-repo/semantics/altIdentifier/url/https://bmcgenomics.biomedcentral.com/articles/10.1186/1471-2164-13-S4-S5info:eu-repo/semantics/altIdentifier/doi/10.1186/1471-2164-13-S4-S5info:eu-repo/semantics/openAccesshttps://creativecommons.org/licenses/by/2.5/ar/reponame:CONICET Digital (CONICET)instname:Consejo Nacional de Investigaciones Científicas y Técnicas2025-10-22T11:24:59Zoai:ri.conicet.gov.ar:11336/273442instacron: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 11:25:00.077CONICET Digital (CONICET) - Consejo Nacional de Investigaciones Científicas y Técnicasfalse
dc.title.none.fl_str_mv On the effect of protein conformation diversity in discriminating among neutral and disease related single amino acid substitutions
title On the effect of protein conformation diversity in discriminating among neutral and disease related single amino acid substitutions
spellingShingle On the effect of protein conformation diversity in discriminating among neutral and disease related single amino acid substitutions
Juritz, Ezequiel
Mutations
Protein stability
Neutral substitutions
Protein conformational diversity
title_short On the effect of protein conformation diversity in discriminating among neutral and disease related single amino acid substitutions
title_full On the effect of protein conformation diversity in discriminating among neutral and disease related single amino acid substitutions
title_fullStr On the effect of protein conformation diversity in discriminating among neutral and disease related single amino acid substitutions
title_full_unstemmed On the effect of protein conformation diversity in discriminating among neutral and disease related single amino acid substitutions
title_sort On the effect of protein conformation diversity in discriminating among neutral and disease related single amino acid substitutions
dc.creator.none.fl_str_mv Juritz, Ezequiel
Fornasari, Maria Silvina
Martelli, Pier Luigi
Fariselli, Piero
Casadio, Rita
Parisi, Gustavo Daniel
author Juritz, Ezequiel
author_facet Juritz, Ezequiel
Fornasari, Maria Silvina
Martelli, Pier Luigi
Fariselli, Piero
Casadio, Rita
Parisi, Gustavo Daniel
author_role author
author2 Fornasari, Maria Silvina
Martelli, Pier Luigi
Fariselli, Piero
Casadio, Rita
Parisi, Gustavo Daniel
author2_role author
author
author
author
author
dc.subject.none.fl_str_mv Mutations
Protein stability
Neutral substitutions
Protein conformational diversity
topic Mutations
Protein stability
Neutral substitutions
Protein conformational diversity
purl_subject.fl_str_mv https://purl.org/becyt/ford/1.6
https://purl.org/becyt/ford/1
dc.description.none.fl_txt_mv Background: Non-synonymous coding SNPs (nsSNPs) that are associated to disease can also be related with alterations in protein stability. Computational methods are available to predict the effect of single amino acid substitutions (SASs) on protein stability based on a single folded structure. However, the native state of a protein is not unique and it is better represented by the ensemble of its conformers in dynamic equilibrium. The maintenance of the ensemble is essential for protein function. In this work we investigated how protein conformational diversity can affect the discrimination of neutral and disease related SASs based on protein stability estimations. For this purpose, we used 119 proteins with 803 associated SASs, 60% of which are disease related. Each protein was associated with its corresponding set of available conformers as found in the Protein Conformational Database (PCDB). Our dataset contains proteins with different extensions of conformational diversity summing up a total number of 1023 conformers. Results: The existence of different conformers for a given protein introduces great variability in the estimation of the protein stability (ΔΔG) after a single amino acid substitution (SAS) as computed with FoldX. Indeed, in 35% of our protein set at least one SAS can be described as stabilizing, destabilizing or neutral when a cutoff value of ±2 kcal/mol is adopted for discriminating neutral from perturbing SASs. However, when the ΔΔG variability among conformers is taken into account, the correlation among the perturbation of protein stability and the corresponding disease or neutral phenotype increases as compared with the same analysis on single protein structures. At the conformer level, we also found that the different conformers correlate in a different way to the corresponding phenotype. Conclusions: Our results suggest that the consideration of conformational diversity can improve the discrimination of neutral and disease related protein SASs based on the evaluation of the corresponding Gibbs free energy change.
Fil: Juritz, Ezequiel. Universidad Nacional de Quilmes. Departamento de Ciencia y Tecnología; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina
Fil: Fornasari, Maria Silvina. Universidad Nacional de Quilmes. Departamento de Ciencia y Tecnología; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina
Fil: Martelli, Pier Luigi. No especifíca;
Fil: Fariselli, Piero. No especifíca;
Fil: Casadio, Rita. No especifíca;
Fil: Parisi, Gustavo Daniel. Universidad Nacional de Quilmes. Departamento de Ciencia y Tecnología; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina
description Background: Non-synonymous coding SNPs (nsSNPs) that are associated to disease can also be related with alterations in protein stability. Computational methods are available to predict the effect of single amino acid substitutions (SASs) on protein stability based on a single folded structure. However, the native state of a protein is not unique and it is better represented by the ensemble of its conformers in dynamic equilibrium. The maintenance of the ensemble is essential for protein function. In this work we investigated how protein conformational diversity can affect the discrimination of neutral and disease related SASs based on protein stability estimations. For this purpose, we used 119 proteins with 803 associated SASs, 60% of which are disease related. Each protein was associated with its corresponding set of available conformers as found in the Protein Conformational Database (PCDB). Our dataset contains proteins with different extensions of conformational diversity summing up a total number of 1023 conformers. Results: The existence of different conformers for a given protein introduces great variability in the estimation of the protein stability (ΔΔG) after a single amino acid substitution (SAS) as computed with FoldX. Indeed, in 35% of our protein set at least one SAS can be described as stabilizing, destabilizing or neutral when a cutoff value of ±2 kcal/mol is adopted for discriminating neutral from perturbing SASs. However, when the ΔΔG variability among conformers is taken into account, the correlation among the perturbation of protein stability and the corresponding disease or neutral phenotype increases as compared with the same analysis on single protein structures. At the conformer level, we also found that the different conformers correlate in a different way to the corresponding phenotype. Conclusions: Our results suggest that the consideration of conformational diversity can improve the discrimination of neutral and disease related protein SASs based on the evaluation of the corresponding Gibbs free energy change.
publishDate 2012
dc.date.none.fl_str_mv 2012-06
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/11336/273442
Juritz, Ezequiel; Fornasari, Maria Silvina; Martelli, Pier Luigi; Fariselli, Piero; Casadio, Rita; et al.; On the effect of protein conformation diversity in discriminating among neutral and disease related single amino acid substitutions; BioMed Central; BMC Genomics; 13; S5; 6-2012; 1-9
1471-2164
CONICET Digital
CONICET
url http://hdl.handle.net/11336/273442
identifier_str_mv Juritz, Ezequiel; Fornasari, Maria Silvina; Martelli, Pier Luigi; Fariselli, Piero; Casadio, Rita; et al.; On the effect of protein conformation diversity in discriminating among neutral and disease related single amino acid substitutions; BioMed Central; BMC Genomics; 13; S5; 6-2012; 1-9
1471-2164
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://bmcgenomics.biomedcentral.com/articles/10.1186/1471-2164-13-S4-S5
info:eu-repo/semantics/altIdentifier/doi/10.1186/1471-2164-13-S4-S5
dc.rights.none.fl_str_mv info:eu-repo/semantics/openAccess
https://creativecommons.org/licenses/by/2.5/ar/
eu_rights_str_mv openAccess
rights_invalid_str_mv https://creativecommons.org/licenses/by/2.5/ar/
dc.format.none.fl_str_mv application/pdf
application/pdf
application/pdf
dc.publisher.none.fl_str_mv BioMed Central
publisher.none.fl_str_mv BioMed Central
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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