Fusing simulation and experiment: The effect of mutations on the structure and activity of the influenza fusion peptide
Autor(a) principal: | |
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Data de Publicação: | 2016 |
Outros Autores: | , , , , , |
Tipo de documento: | Artigo |
Idioma: | eng |
Título da fonte: | Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos) |
Texto Completo: | http://hdl.handle.net/10316/108916 https://doi.org/10.1038/srep28099 |
Resumo: | During the infection process, the influenza fusion peptide (FP) inserts into the host membrane, playing a crucial role in the fusion process between the viral and host membranes. In this work we used a combination of simulation and experimental techniques to analyse the molecular details of this process, which are largely unknown. Although the FP structure has been obtained by NMR in detergent micelles, there is no atomic structure information in membranes. To answer this question, we performed bias-exchange metadynamics (BE-META) simulations, which showed that the lowest energy states of the membrane-inserted FP correspond to helical-hairpin conformations similar to that observed in micelles. BE-META simulations of the G1V, W14A, G12A/G13A and G4A/G8A/G16A/G20A mutants revealed that all the mutations affect the peptide's free energy landscape. A FRET-based analysis showed that all the mutants had a reduced fusogenic activity relative to the WT, in particular the mutants G12A/G13A and G4A/G8A/G16A/G20A. According to our results, one of the major causes of the lower activity of these mutants is their lower membrane affinity, which results in a lower concentration of peptide in the bilayer. These findings contribute to a better understanding of the influenza fusion process and open new routes for future studies. |
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Fusing simulation and experiment: The effect of mutations on the structure and activity of the influenza fusion peptideInfluenza A virusMagnetic Resonance SpectroscopyModels, MolecularMolecular Dynamics SimulationMolecular StructurePeptidesSpectrometry, FluorescenceViral Fusion ProteinsVirus InternalizationMutationDuring the infection process, the influenza fusion peptide (FP) inserts into the host membrane, playing a crucial role in the fusion process between the viral and host membranes. In this work we used a combination of simulation and experimental techniques to analyse the molecular details of this process, which are largely unknown. Although the FP structure has been obtained by NMR in detergent micelles, there is no atomic structure information in membranes. To answer this question, we performed bias-exchange metadynamics (BE-META) simulations, which showed that the lowest energy states of the membrane-inserted FP correspond to helical-hairpin conformations similar to that observed in micelles. BE-META simulations of the G1V, W14A, G12A/G13A and G4A/G8A/G16A/G20A mutants revealed that all the mutations affect the peptide's free energy landscape. A FRET-based analysis showed that all the mutants had a reduced fusogenic activity relative to the WT, in particular the mutants G12A/G13A and G4A/G8A/G16A/G20A. According to our results, one of the major causes of the lower activity of these mutants is their lower membrane affinity, which results in a lower concentration of peptide in the bilayer. These findings contribute to a better understanding of the influenza fusion process and open new routes for future studies.Springer Nature2016-06-15info:eu-repo/semantics/publishedVersioninfo:eu-repo/semantics/articlehttp://hdl.handle.net/10316/108916http://hdl.handle.net/10316/108916https://doi.org/10.1038/srep28099eng2045-2322Lousa, DianaPinto, Antónia R TVictor, Bruno L.Laio, AlessandroVeiga, Ana S.Castanho, Miguel A. R. B.Soares, Cláudio M.info:eu-repo/semantics/openAccessreponame:Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos)instname:Agência para a Sociedade do Conhecimento (UMIC) - FCT - Sociedade da Informaçãoinstacron:RCAAP2023-09-25T09:03:57Zoai:estudogeral.uc.pt:10316/108916Portal AgregadorONGhttps://www.rcaap.pt/oai/openaireopendoar:71602024-03-19T21:25:09.211128Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos) - Agência para a Sociedade do Conhecimento (UMIC) - FCT - Sociedade da Informaçãofalse |
dc.title.none.fl_str_mv |
Fusing simulation and experiment: The effect of mutations on the structure and activity of the influenza fusion peptide |
title |
Fusing simulation and experiment: The effect of mutations on the structure and activity of the influenza fusion peptide |
spellingShingle |
Fusing simulation and experiment: The effect of mutations on the structure and activity of the influenza fusion peptide Lousa, Diana Influenza A virus Magnetic Resonance Spectroscopy Models, Molecular Molecular Dynamics Simulation Molecular Structure Peptides Spectrometry, Fluorescence Viral Fusion Proteins Virus Internalization Mutation |
title_short |
Fusing simulation and experiment: The effect of mutations on the structure and activity of the influenza fusion peptide |
title_full |
Fusing simulation and experiment: The effect of mutations on the structure and activity of the influenza fusion peptide |
title_fullStr |
Fusing simulation and experiment: The effect of mutations on the structure and activity of the influenza fusion peptide |
title_full_unstemmed |
Fusing simulation and experiment: The effect of mutations on the structure and activity of the influenza fusion peptide |
title_sort |
Fusing simulation and experiment: The effect of mutations on the structure and activity of the influenza fusion peptide |
author |
Lousa, Diana |
author_facet |
Lousa, Diana Pinto, Antónia R T Victor, Bruno L. Laio, Alessandro Veiga, Ana S. Castanho, Miguel A. R. B. Soares, Cláudio M. |
author_role |
author |
author2 |
Pinto, Antónia R T Victor, Bruno L. Laio, Alessandro Veiga, Ana S. Castanho, Miguel A. R. B. Soares, Cláudio M. |
author2_role |
author author author author author author |
dc.contributor.author.fl_str_mv |
Lousa, Diana Pinto, Antónia R T Victor, Bruno L. Laio, Alessandro Veiga, Ana S. Castanho, Miguel A. R. B. Soares, Cláudio M. |
dc.subject.por.fl_str_mv |
Influenza A virus Magnetic Resonance Spectroscopy Models, Molecular Molecular Dynamics Simulation Molecular Structure Peptides Spectrometry, Fluorescence Viral Fusion Proteins Virus Internalization Mutation |
topic |
Influenza A virus Magnetic Resonance Spectroscopy Models, Molecular Molecular Dynamics Simulation Molecular Structure Peptides Spectrometry, Fluorescence Viral Fusion Proteins Virus Internalization Mutation |
description |
During the infection process, the influenza fusion peptide (FP) inserts into the host membrane, playing a crucial role in the fusion process between the viral and host membranes. In this work we used a combination of simulation and experimental techniques to analyse the molecular details of this process, which are largely unknown. Although the FP structure has been obtained by NMR in detergent micelles, there is no atomic structure information in membranes. To answer this question, we performed bias-exchange metadynamics (BE-META) simulations, which showed that the lowest energy states of the membrane-inserted FP correspond to helical-hairpin conformations similar to that observed in micelles. BE-META simulations of the G1V, W14A, G12A/G13A and G4A/G8A/G16A/G20A mutants revealed that all the mutations affect the peptide's free energy landscape. A FRET-based analysis showed that all the mutants had a reduced fusogenic activity relative to the WT, in particular the mutants G12A/G13A and G4A/G8A/G16A/G20A. According to our results, one of the major causes of the lower activity of these mutants is their lower membrane affinity, which results in a lower concentration of peptide in the bilayer. These findings contribute to a better understanding of the influenza fusion process and open new routes for future studies. |
publishDate |
2016 |
dc.date.none.fl_str_mv |
2016-06-15 |
dc.type.status.fl_str_mv |
info:eu-repo/semantics/publishedVersion |
dc.type.driver.fl_str_mv |
info:eu-repo/semantics/article |
format |
article |
status_str |
publishedVersion |
dc.identifier.uri.fl_str_mv |
http://hdl.handle.net/10316/108916 http://hdl.handle.net/10316/108916 https://doi.org/10.1038/srep28099 |
url |
http://hdl.handle.net/10316/108916 https://doi.org/10.1038/srep28099 |
dc.language.iso.fl_str_mv |
eng |
language |
eng |
dc.relation.none.fl_str_mv |
2045-2322 |
dc.rights.driver.fl_str_mv |
info:eu-repo/semantics/openAccess |
eu_rights_str_mv |
openAccess |
dc.publisher.none.fl_str_mv |
Springer Nature |
publisher.none.fl_str_mv |
Springer Nature |
dc.source.none.fl_str_mv |
reponame:Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos) instname:Agência para a Sociedade do Conhecimento (UMIC) - FCT - Sociedade da Informação instacron:RCAAP |
instname_str |
Agência para a Sociedade do Conhecimento (UMIC) - FCT - Sociedade da Informação |
instacron_str |
RCAAP |
institution |
RCAAP |
reponame_str |
Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos) |
collection |
Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos) |
repository.name.fl_str_mv |
Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos) - Agência para a Sociedade do Conhecimento (UMIC) - FCT - Sociedade da Informação |
repository.mail.fl_str_mv |
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1799134134461792256 |