Permeability of the HIV-1 capsid to metabolites modulates viral DNA synthesis.
Reverse transcription, an essential event in the HIV-1 life cycle, requires deoxynucleotide triphosphates (dNTPs) to fuel DNA synthesis, thus requiring penetration of dNTPs into the viral capsid. The central cavity of the capsid protein (CA) hexamer reveals itself as a plausible channel that allows...
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2020-12-01
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Online Access: | https://doi.org/10.1371/journal.pbio.3001015 |
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doaj-1aa20b004af54e01aac2ef7867b6cf2f2021-07-02T19:28:46ZengPublic Library of Science (PLoS)PLoS Biology1544-91731545-78852020-12-011812e300101510.1371/journal.pbio.3001015Permeability of the HIV-1 capsid to metabolites modulates viral DNA synthesis.Chaoyi XuDouglas K FischerSanela RankovicWen LiRobert A DickBrent RungeRoman ZadorozhnyiJinwoo AhnChristopher AikenTatyana PolenovaAlan N EngelmanZandrea AmbroseItay RoussoJuan R PerillaReverse transcription, an essential event in the HIV-1 life cycle, requires deoxynucleotide triphosphates (dNTPs) to fuel DNA synthesis, thus requiring penetration of dNTPs into the viral capsid. The central cavity of the capsid protein (CA) hexamer reveals itself as a plausible channel that allows the passage of dNTPs into assembled capsids. Nevertheless, the molecular mechanism of nucleotide import into the capsid remains unknown. Employing all-atom molecular dynamics (MD) simulations, we established that cooperative binding between nucleotides inside a CA hexamer cavity results in energetically favorable conditions for passive translocation of dNTPs into the HIV-1 capsid. Furthermore, binding of the host cell metabolite inositol hexakisphosphate (IP6) enhances dNTP import, while binding of synthesized molecules like benzenehexacarboxylic acid (BHC) inhibits it. The enhancing effect on reverse transcription by IP6 and the consequences of interactions between CA and nucleotides were corroborated using atomic force microscopy, transmission electron microscopy, and virological assays. Collectively, our results provide an atomistic description of the permeability of the HIV-1 capsid to small molecules and reveal a novel mechanism for the involvement of metabolites in HIV-1 capsid stabilization, nucleotide import, and reverse transcription.https://doi.org/10.1371/journal.pbio.3001015 |
collection |
DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
Chaoyi Xu Douglas K Fischer Sanela Rankovic Wen Li Robert A Dick Brent Runge Roman Zadorozhnyi Jinwoo Ahn Christopher Aiken Tatyana Polenova Alan N Engelman Zandrea Ambrose Itay Rousso Juan R Perilla |
spellingShingle |
Chaoyi Xu Douglas K Fischer Sanela Rankovic Wen Li Robert A Dick Brent Runge Roman Zadorozhnyi Jinwoo Ahn Christopher Aiken Tatyana Polenova Alan N Engelman Zandrea Ambrose Itay Rousso Juan R Perilla Permeability of the HIV-1 capsid to metabolites modulates viral DNA synthesis. PLoS Biology |
author_facet |
Chaoyi Xu Douglas K Fischer Sanela Rankovic Wen Li Robert A Dick Brent Runge Roman Zadorozhnyi Jinwoo Ahn Christopher Aiken Tatyana Polenova Alan N Engelman Zandrea Ambrose Itay Rousso Juan R Perilla |
author_sort |
Chaoyi Xu |
title |
Permeability of the HIV-1 capsid to metabolites modulates viral DNA synthesis. |
title_short |
Permeability of the HIV-1 capsid to metabolites modulates viral DNA synthesis. |
title_full |
Permeability of the HIV-1 capsid to metabolites modulates viral DNA synthesis. |
title_fullStr |
Permeability of the HIV-1 capsid to metabolites modulates viral DNA synthesis. |
title_full_unstemmed |
Permeability of the HIV-1 capsid to metabolites modulates viral DNA synthesis. |
title_sort |
permeability of the hiv-1 capsid to metabolites modulates viral dna synthesis. |
publisher |
Public Library of Science (PLoS) |
series |
PLoS Biology |
issn |
1544-9173 1545-7885 |
publishDate |
2020-12-01 |
description |
Reverse transcription, an essential event in the HIV-1 life cycle, requires deoxynucleotide triphosphates (dNTPs) to fuel DNA synthesis, thus requiring penetration of dNTPs into the viral capsid. The central cavity of the capsid protein (CA) hexamer reveals itself as a plausible channel that allows the passage of dNTPs into assembled capsids. Nevertheless, the molecular mechanism of nucleotide import into the capsid remains unknown. Employing all-atom molecular dynamics (MD) simulations, we established that cooperative binding between nucleotides inside a CA hexamer cavity results in energetically favorable conditions for passive translocation of dNTPs into the HIV-1 capsid. Furthermore, binding of the host cell metabolite inositol hexakisphosphate (IP6) enhances dNTP import, while binding of synthesized molecules like benzenehexacarboxylic acid (BHC) inhibits it. The enhancing effect on reverse transcription by IP6 and the consequences of interactions between CA and nucleotides were corroborated using atomic force microscopy, transmission electron microscopy, and virological assays. Collectively, our results provide an atomistic description of the permeability of the HIV-1 capsid to small molecules and reveal a novel mechanism for the involvement of metabolites in HIV-1 capsid stabilization, nucleotide import, and reverse transcription. |
url |
https://doi.org/10.1371/journal.pbio.3001015 |
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