A funneled conformational landscape governs flavivirus fusion peptide interaction with lipid membranes

During host cell infection by flaviviruses such as dengue and Zika, acidic pH within the endosome triggers a conformational change in the envelope protein on the outer surface of the virion. This results in exposure of the ∼15 residue fusion peptide (FP) region, freeing it to induce fusion between t...

Full description

Saved in:
Bibliographic Details
Main Authors: Marzinek, Jan Kazimierz, Bag, Nirmalya, Huber, Roland G., Holdbrook, Daniel A., Wohland, Thorsten, Verma, Chandra Shekhar, Bond, Peter John
Other Authors: School of Biological Sciences
Format: Article
Language:English
Published: 2020
Subjects:
Online Access:https://hdl.handle.net/10356/139524
Tags: Add Tag
No Tags, Be the first to tag this record!
Institution: Nanyang Technological University
Language: English
id sg-ntu-dr.10356-139524
record_format dspace
spelling sg-ntu-dr.10356-1395242020-05-20T03:44:09Z A funneled conformational landscape governs flavivirus fusion peptide interaction with lipid membranes Marzinek, Jan Kazimierz Bag, Nirmalya Huber, Roland G. Holdbrook, Daniel A. Wohland, Thorsten Verma, Chandra Shekhar Bond, Peter John School of Biological Sciences Science::Biological sciences Vesicles Lipids During host cell infection by flaviviruses such as dengue and Zika, acidic pH within the endosome triggers a conformational change in the envelope protein on the outer surface of the virion. This results in exposure of the ∼15 residue fusion peptide (FP) region, freeing it to induce fusion between the viral and endosomal membranes. A better understanding of the conformational dynamics of the FP in the presence of membranes, and the basis for its selectivity for anionic lipid species present within the endosome, would facilitate its therapeutic targeting with antiviral drugs and antibodies. In this work, multiscale modeling, simulations, and free energy calculations (including a total of ∼75 μs of atomic-resolution sampling), combined with imaging total internal reflection fluorescence correlation spectroscopy experiments, were employed to investigate the mechanisms of interaction of FP variants with lipid bilayers. Wild-type FPs (in the presence or absence of a fluorescein isothiocyanate tag) were shown to possess a funneled conformational landscape governing their exit from solvent and penetration into the lipid phase and to exhibit an electrostatically favored >2-fold affinity for membranes containing anionic species over purely zwitterionic ones. Conversely, the landscape was abolished in a nonfunctional point mutant, leading to a 2-fold drop in host membrane affinity. Collectively, our data reveal how the highly conserved flavivirus FP has evolved to funnel its conformational space toward a maximally fusogenic state anchored within the endosomal membrane. Therapeutically targeting the accessible ensemble of FP conformations may represent a new, rational strategy for blocking viral infection. 2020-05-20T03:44:09Z 2020-05-20T03:44:09Z 2018 Journal Article Marzinek, J. K., Bag, N., Huber, R. G., Holdbrook, D. A., Wohland, T., Verma, C. S., & Bond, P. J. (2018). A funneled conformational landscape governs flavivirus fusion peptide interaction with lipid membranes. Journal of Chemical Theory and Computation, 14(7), 3920-3932. doi:10.1021/acs.jctc.8b00438 1549-9618 https://hdl.handle.net/10356/139524 10.1021/acs.jctc.8b00438 29874075 2-s2.0-85048372030 7 14 3920 3932 en Journal of Chemical Theory and Computation © 2018 American Chemical Society. All rights reserved.
institution Nanyang Technological University
building NTU Library
country Singapore
collection DR-NTU
language English
topic Science::Biological sciences
Vesicles
Lipids
spellingShingle Science::Biological sciences
Vesicles
Lipids
Marzinek, Jan Kazimierz
Bag, Nirmalya
Huber, Roland G.
Holdbrook, Daniel A.
Wohland, Thorsten
Verma, Chandra Shekhar
Bond, Peter John
A funneled conformational landscape governs flavivirus fusion peptide interaction with lipid membranes
description During host cell infection by flaviviruses such as dengue and Zika, acidic pH within the endosome triggers a conformational change in the envelope protein on the outer surface of the virion. This results in exposure of the ∼15 residue fusion peptide (FP) region, freeing it to induce fusion between the viral and endosomal membranes. A better understanding of the conformational dynamics of the FP in the presence of membranes, and the basis for its selectivity for anionic lipid species present within the endosome, would facilitate its therapeutic targeting with antiviral drugs and antibodies. In this work, multiscale modeling, simulations, and free energy calculations (including a total of ∼75 μs of atomic-resolution sampling), combined with imaging total internal reflection fluorescence correlation spectroscopy experiments, were employed to investigate the mechanisms of interaction of FP variants with lipid bilayers. Wild-type FPs (in the presence or absence of a fluorescein isothiocyanate tag) were shown to possess a funneled conformational landscape governing their exit from solvent and penetration into the lipid phase and to exhibit an electrostatically favored >2-fold affinity for membranes containing anionic species over purely zwitterionic ones. Conversely, the landscape was abolished in a nonfunctional point mutant, leading to a 2-fold drop in host membrane affinity. Collectively, our data reveal how the highly conserved flavivirus FP has evolved to funnel its conformational space toward a maximally fusogenic state anchored within the endosomal membrane. Therapeutically targeting the accessible ensemble of FP conformations may represent a new, rational strategy for blocking viral infection.
author2 School of Biological Sciences
author_facet School of Biological Sciences
Marzinek, Jan Kazimierz
Bag, Nirmalya
Huber, Roland G.
Holdbrook, Daniel A.
Wohland, Thorsten
Verma, Chandra Shekhar
Bond, Peter John
format Article
author Marzinek, Jan Kazimierz
Bag, Nirmalya
Huber, Roland G.
Holdbrook, Daniel A.
Wohland, Thorsten
Verma, Chandra Shekhar
Bond, Peter John
author_sort Marzinek, Jan Kazimierz
title A funneled conformational landscape governs flavivirus fusion peptide interaction with lipid membranes
title_short A funneled conformational landscape governs flavivirus fusion peptide interaction with lipid membranes
title_full A funneled conformational landscape governs flavivirus fusion peptide interaction with lipid membranes
title_fullStr A funneled conformational landscape governs flavivirus fusion peptide interaction with lipid membranes
title_full_unstemmed A funneled conformational landscape governs flavivirus fusion peptide interaction with lipid membranes
title_sort funneled conformational landscape governs flavivirus fusion peptide interaction with lipid membranes
publishDate 2020
url https://hdl.handle.net/10356/139524
_version_ 1681056040113668096