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Breathing and tilting: mesoscale simulations illuminate influenza glycoprotein vulnerabilities

Influenza virus has resurfaced recently from inactivity during the early stages of the COVID-19 pandemic, raising serious concerns about the nature and magnitude of future epidemics. The main antigenic targets of influenza virus are two surface glycoproteins, hemagglutinin (HA) and neuraminidase (NA...

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Autores principales: Casalino, Lorenzo, Seitz, Christian, Lederhofer, Julia, Tsybovsky, Yaroslav, Wilson, Ian A., Kanekiyo, Masaru, Amaro, Rommie E.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Cold Spring Harbor Laboratory 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9387122/
https://www.ncbi.nlm.nih.gov/pubmed/35982676
http://dx.doi.org/10.1101/2022.08.02.502576
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author Casalino, Lorenzo
Seitz, Christian
Lederhofer, Julia
Tsybovsky, Yaroslav
Wilson, Ian A.
Kanekiyo, Masaru
Amaro, Rommie E.
author_facet Casalino, Lorenzo
Seitz, Christian
Lederhofer, Julia
Tsybovsky, Yaroslav
Wilson, Ian A.
Kanekiyo, Masaru
Amaro, Rommie E.
author_sort Casalino, Lorenzo
collection PubMed
description Influenza virus has resurfaced recently from inactivity during the early stages of the COVID-19 pandemic, raising serious concerns about the nature and magnitude of future epidemics. The main antigenic targets of influenza virus are two surface glycoproteins, hemagglutinin (HA) and neuraminidase (NA). Whereas the structural and dynamical properties of both glycoproteins have been studied previously, the understanding of their plasticity in the whole-virion context is fragmented. Here, we investigate the dynamics of influenza glycoproteins in a crowded protein environment through mesoscale all-atom molecular dynamics simulations of two evolutionary-linked glycosylated influenza A whole-virion models. Our simulations reveal and kinetically characterize three main molecular motions of influenza glycoproteins: NA head tilting, HA ectodomain tilting, and HA head breathing. The flexibility of HA and NA highlights antigenically relevant conformational states, as well as facilitates the characterization of a novel monoclonal antibody, derived from human convalescent plasma, that binds to the underside of the NA head. Our work provides previously unappreciated views on the dynamics of HA and NA, advancing the understanding of their interplay and suggesting possible strategies for the design of future vaccines and antivirals against influenza.
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spelling pubmed-93871222022-08-19 Breathing and tilting: mesoscale simulations illuminate influenza glycoprotein vulnerabilities Casalino, Lorenzo Seitz, Christian Lederhofer, Julia Tsybovsky, Yaroslav Wilson, Ian A. Kanekiyo, Masaru Amaro, Rommie E. bioRxiv Article Influenza virus has resurfaced recently from inactivity during the early stages of the COVID-19 pandemic, raising serious concerns about the nature and magnitude of future epidemics. The main antigenic targets of influenza virus are two surface glycoproteins, hemagglutinin (HA) and neuraminidase (NA). Whereas the structural and dynamical properties of both glycoproteins have been studied previously, the understanding of their plasticity in the whole-virion context is fragmented. Here, we investigate the dynamics of influenza glycoproteins in a crowded protein environment through mesoscale all-atom molecular dynamics simulations of two evolutionary-linked glycosylated influenza A whole-virion models. Our simulations reveal and kinetically characterize three main molecular motions of influenza glycoproteins: NA head tilting, HA ectodomain tilting, and HA head breathing. The flexibility of HA and NA highlights antigenically relevant conformational states, as well as facilitates the characterization of a novel monoclonal antibody, derived from human convalescent plasma, that binds to the underside of the NA head. Our work provides previously unappreciated views on the dynamics of HA and NA, advancing the understanding of their interplay and suggesting possible strategies for the design of future vaccines and antivirals against influenza. Cold Spring Harbor Laboratory 2022-08-07 /pmc/articles/PMC9387122/ /pubmed/35982676 http://dx.doi.org/10.1101/2022.08.02.502576 Text en https://creativecommons.org/licenses/by-nd/4.0/This work is licensed under a Creative Commons Attribution-NoDerivatives 4.0 International License (https://creativecommons.org/licenses/by-nd/4.0/) , which allows reusers to copy and distribute the material in any medium or format in unadapted form only, and only so long as attribution is given to the creator. The license allows for commercial use.
spellingShingle Article
Casalino, Lorenzo
Seitz, Christian
Lederhofer, Julia
Tsybovsky, Yaroslav
Wilson, Ian A.
Kanekiyo, Masaru
Amaro, Rommie E.
Breathing and tilting: mesoscale simulations illuminate influenza glycoprotein vulnerabilities
title Breathing and tilting: mesoscale simulations illuminate influenza glycoprotein vulnerabilities
title_full Breathing and tilting: mesoscale simulations illuminate influenza glycoprotein vulnerabilities
title_fullStr Breathing and tilting: mesoscale simulations illuminate influenza glycoprotein vulnerabilities
title_full_unstemmed Breathing and tilting: mesoscale simulations illuminate influenza glycoprotein vulnerabilities
title_short Breathing and tilting: mesoscale simulations illuminate influenza glycoprotein vulnerabilities
title_sort breathing and tilting: mesoscale simulations illuminate influenza glycoprotein vulnerabilities
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9387122/
https://www.ncbi.nlm.nih.gov/pubmed/35982676
http://dx.doi.org/10.1101/2022.08.02.502576
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