Cargando…

Effect of pH on the influenza fusion peptide properties unveiled by constant-pH molecular dynamics simulations combined with experiment

The influenza virus fusion process, whereby the virus fuses its envelope with the host endosome membrane to release the genetic material, takes place in the acidic late endosome environment. Acidification triggers a large conformational change in the fusion protein, hemagglutinin (HA), which enables...

Descripción completa

Detalles Bibliográficos
Autores principales: Lousa, Diana, Pinto, Antónia R. T., Campos, Sara R. R., Baptista, António M., Veiga, Ana S., Castanho, Miguel A. R. B., Soares, Cláudio M.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Publishing Group UK 2020
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7674464/
https://www.ncbi.nlm.nih.gov/pubmed/33208852
http://dx.doi.org/10.1038/s41598-020-77040-y
_version_ 1783611511742136320
author Lousa, Diana
Pinto, Antónia R. T.
Campos, Sara R. R.
Baptista, António M.
Veiga, Ana S.
Castanho, Miguel A. R. B.
Soares, Cláudio M.
author_facet Lousa, Diana
Pinto, Antónia R. T.
Campos, Sara R. R.
Baptista, António M.
Veiga, Ana S.
Castanho, Miguel A. R. B.
Soares, Cláudio M.
author_sort Lousa, Diana
collection PubMed
description The influenza virus fusion process, whereby the virus fuses its envelope with the host endosome membrane to release the genetic material, takes place in the acidic late endosome environment. Acidification triggers a large conformational change in the fusion protein, hemagglutinin (HA), which enables the insertion of the N-terminal region of the HA2 subunit, known as the fusion peptide, into the membrane of the host endosome. However, the mechanism by which pH modulates the molecular properties of the fusion peptide remains unclear. To answer this question, we performed the first constant-pH molecular dynamics simulations of the influenza fusion peptide in a membrane, extending for 40 µs of aggregated time. The simulations were combined with spectroscopic data, which showed that the peptide is twofold more active in promoting lipid mixing of model membranes at pH 5 than at pH 7.4. The realistic treatment of protonation introduced by the constant-pH molecular dynamics simulations revealed that low pH stabilizes a vertical membrane-spanning conformation and leads to more frequent contacts between the fusion peptide and the lipid headgroups, which may explain the increase in activity. The study also revealed that the N-terminal region is determinant for the peptide’s effect on the membrane.
format Online
Article
Text
id pubmed-7674464
institution National Center for Biotechnology Information
language English
publishDate 2020
publisher Nature Publishing Group UK
record_format MEDLINE/PubMed
spelling pubmed-76744642020-11-19 Effect of pH on the influenza fusion peptide properties unveiled by constant-pH molecular dynamics simulations combined with experiment Lousa, Diana Pinto, Antónia R. T. Campos, Sara R. R. Baptista, António M. Veiga, Ana S. Castanho, Miguel A. R. B. Soares, Cláudio M. Sci Rep Article The influenza virus fusion process, whereby the virus fuses its envelope with the host endosome membrane to release the genetic material, takes place in the acidic late endosome environment. Acidification triggers a large conformational change in the fusion protein, hemagglutinin (HA), which enables the insertion of the N-terminal region of the HA2 subunit, known as the fusion peptide, into the membrane of the host endosome. However, the mechanism by which pH modulates the molecular properties of the fusion peptide remains unclear. To answer this question, we performed the first constant-pH molecular dynamics simulations of the influenza fusion peptide in a membrane, extending for 40 µs of aggregated time. The simulations were combined with spectroscopic data, which showed that the peptide is twofold more active in promoting lipid mixing of model membranes at pH 5 than at pH 7.4. The realistic treatment of protonation introduced by the constant-pH molecular dynamics simulations revealed that low pH stabilizes a vertical membrane-spanning conformation and leads to more frequent contacts between the fusion peptide and the lipid headgroups, which may explain the increase in activity. The study also revealed that the N-terminal region is determinant for the peptide’s effect on the membrane. Nature Publishing Group UK 2020-11-18 /pmc/articles/PMC7674464/ /pubmed/33208852 http://dx.doi.org/10.1038/s41598-020-77040-y Text en © The Author(s) 2020 https://creativecommons.org/licenses/by/4.0/Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) .
spellingShingle Article
Lousa, Diana
Pinto, Antónia R. T.
Campos, Sara R. R.
Baptista, António M.
Veiga, Ana S.
Castanho, Miguel A. R. B.
Soares, Cláudio M.
Effect of pH on the influenza fusion peptide properties unveiled by constant-pH molecular dynamics simulations combined with experiment
title Effect of pH on the influenza fusion peptide properties unveiled by constant-pH molecular dynamics simulations combined with experiment
title_full Effect of pH on the influenza fusion peptide properties unveiled by constant-pH molecular dynamics simulations combined with experiment
title_fullStr Effect of pH on the influenza fusion peptide properties unveiled by constant-pH molecular dynamics simulations combined with experiment
title_full_unstemmed Effect of pH on the influenza fusion peptide properties unveiled by constant-pH molecular dynamics simulations combined with experiment
title_short Effect of pH on the influenza fusion peptide properties unveiled by constant-pH molecular dynamics simulations combined with experiment
title_sort effect of ph on the influenza fusion peptide properties unveiled by constant-ph molecular dynamics simulations combined with experiment
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7674464/
https://www.ncbi.nlm.nih.gov/pubmed/33208852
http://dx.doi.org/10.1038/s41598-020-77040-y
work_keys_str_mv AT lousadiana effectofphontheinfluenzafusionpeptidepropertiesunveiledbyconstantphmoleculardynamicssimulationscombinedwithexperiment
AT pintoantoniart effectofphontheinfluenzafusionpeptidepropertiesunveiledbyconstantphmoleculardynamicssimulationscombinedwithexperiment
AT campossararr effectofphontheinfluenzafusionpeptidepropertiesunveiledbyconstantphmoleculardynamicssimulationscombinedwithexperiment
AT baptistaantoniom effectofphontheinfluenzafusionpeptidepropertiesunveiledbyconstantphmoleculardynamicssimulationscombinedwithexperiment
AT veigaanas effectofphontheinfluenzafusionpeptidepropertiesunveiledbyconstantphmoleculardynamicssimulationscombinedwithexperiment
AT castanhomiguelarb effectofphontheinfluenzafusionpeptidepropertiesunveiledbyconstantphmoleculardynamicssimulationscombinedwithexperiment
AT soaresclaudiom effectofphontheinfluenzafusionpeptidepropertiesunveiledbyconstantphmoleculardynamicssimulationscombinedwithexperiment