Computational Model and Dynamics of Monomeric Full-Length APOBEC3G

Suresh Gorle, Yangang Pan, Zhiqiang Sun, Luda S. Shlyakhtenko, Reuben S. Harris, Yuri L. Lyubchenko, Lela Vuković

Research output: Contribution to journalArticle

7 Citations (Scopus)

Abstract

APOBEC3G (A3G) is a restriction factor that provides innate immunity against HIV-1 in the absence of viral infectivity factor (Vif) protein. However, structural information about A3G, which can aid in unraveling the mechanisms that govern its interactions and define its antiviral activity, remains unknown. Here, we built a computer model of a full-length A3G using docking approaches and molecular dynamics simulations, based on the available X-ray and NMR structural data for the two protein domains. The model revealed a large-scale dynamics of the A3G monomer, as the two A3G domains can assume compact forms or extended dumbbell type forms with domains visibly separated from each other. To validate the A3G model, we performed time-lapse high-speed atomic force microscopy (HS-AFM) experiments enabling us to get images of a fully hydrated A3G and to directly visualize its dynamics. HS-AFM confirmed that A3G exists in two forms, a globular form (∼84% of the time) and a dumbbell form (∼16% of the time), and can dynamically switch from one form to the other. The obtained HS-AFM results are in line with the computer modeling, which demonstrates a similar distribution between two forms. Furthermore, our simulations capture the complete process of A3G switching from the DNA-bound state to the closed state. The revealed dynamic nature of monomeric A3G could aid in target recognition including scanning for cytosine locations along the DNA strand and in interactions with viral RNA during packaging into HIV-1 particles.

Original languageEnglish (US)
Pages (from-to)1180-1188
Number of pages9
JournalACS Central Science
Volume3
Issue number11
DOIs
StatePublished - Nov 22 2017
Externally publishedYes

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Atomic force microscopy
DNA
Proteins
Cytosine
Viral RNA
RNA
Antiviral Agents
Molecular dynamics
Packaging
Monomers
Switches
Nuclear magnetic resonance
Scanning
X rays
Computer simulation
Experiments

ASJC Scopus subject areas

  • Chemistry(all)
  • Chemical Engineering(all)

Cite this

Gorle, S., Pan, Y., Sun, Z., Shlyakhtenko, L. S., Harris, R. S., Lyubchenko, Y. L., & Vuković, L. (2017). Computational Model and Dynamics of Monomeric Full-Length APOBEC3G. ACS Central Science, 3(11), 1180-1188. https://doi.org/10.1021/acscentsci.7b00346

Computational Model and Dynamics of Monomeric Full-Length APOBEC3G. / Gorle, Suresh; Pan, Yangang; Sun, Zhiqiang; Shlyakhtenko, Luda S.; Harris, Reuben S.; Lyubchenko, Yuri L.; Vuković, Lela.

In: ACS Central Science, Vol. 3, No. 11, 22.11.2017, p. 1180-1188.

Research output: Contribution to journalArticle

Gorle, S, Pan, Y, Sun, Z, Shlyakhtenko, LS, Harris, RS, Lyubchenko, YL & Vuković, L 2017, 'Computational Model and Dynamics of Monomeric Full-Length APOBEC3G', ACS Central Science, vol. 3, no. 11, pp. 1180-1188. https://doi.org/10.1021/acscentsci.7b00346
Gorle S, Pan Y, Sun Z, Shlyakhtenko LS, Harris RS, Lyubchenko YL et al. Computational Model and Dynamics of Monomeric Full-Length APOBEC3G. ACS Central Science. 2017 Nov 22;3(11):1180-1188. https://doi.org/10.1021/acscentsci.7b00346
Gorle, Suresh ; Pan, Yangang ; Sun, Zhiqiang ; Shlyakhtenko, Luda S. ; Harris, Reuben S. ; Lyubchenko, Yuri L. ; Vuković, Lela. / Computational Model and Dynamics of Monomeric Full-Length APOBEC3G. In: ACS Central Science. 2017 ; Vol. 3, No. 11. pp. 1180-1188.
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