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In silico analysis of the defensive potential of dGTPases in Wolbachia against viral infections through a molecular docking study
Análisis in silico del potencial defensivo de las dGTPasas en Wolbachia contra infecciones virales mediante un estudio de acoplamiento molecular
Análise in silico do potencial defensivo das dGTPases em Wolbachia contra infecções virais por meio de um estudo de acoplamento molecular
DOI:
https://doi.org/10.15446/rcciquifa.v55n3.119988Palabras clave:
molecular docking, pan-inmune, system defense antiviral, depletion, bioinformatics (en)Paninmune, sistema de defensa antiviral, depleción, acoplamiento molecular, bioinformática (es)
Panimune, sistema de defesa antiviral, depleção, docking molecular, bioinformática (pt)
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Introduction: Wolbachia is an endosymbiont that protects its host against viral infections, although the underlying mechanisms remain unclear. This in silico study explores the presence of antiviral defense systems in Wolbachia, with emphasis on dGTPases, enzymes that degrade dGTP, an essential nucleotide for viral replication. Methodology: Using PADLOC and DefenseFinder, 194 complete Wolbachia genomes were analyzed and defense systems were identified. The structures of dGTPases from Wolbachia, R. felis, S. putrefaciens and E. coli were predicted with Protenix and docked with dGTP using HADDOCK 2.4. Interactions were characterized with PLIP, affinity with PRODIGY‑LIG, and in silico mutagenesis was performed in E. coli. Results: The dGTPase system is present in 99% of strains carrying defense systems. The Wolbachia dGTPase showed the best HADDOCK score (-30.2), a very negative electrostatic energy (-128.1 kcal/mol) and a compact Mn²⁺ coordination (square planar, distances ≤2.44 Å) with three salt bridges. R. felis presented a similar score (-29.2) but a lower electrostatic component (-44.9 kcal/mol). The free‑living dGTPases (S. putrefaciens and E. coli) showed less favorable scores (-22.3 and -21.5). Mutagenesis (Phe391→Tyr, Glu400→Met) in E. coli did not reproduce the high affinity of Wolbachia. Conclusion: The Wolbachia dGTPase suggests a structural specialization that makes it particularly efficient in dGTP binding, suggesting a role in dNTP depletion as an antiviral mechanism.
Introducción: Wolbachia es un endosimbionte que protege a su huésped frente a infecciones virales, aunque los mecanismos subyacentes no están del todo claros. En este estudio in silico se explora la presencia de sistemas de defensa antiviral en Wolbachia, con énfasis en las dGTPasas, enzimas que degradan dGTP, un nucleótido esencial para la replicación viral. Metodología: Mediante PADLOC y DefenseFinder se analizaron 194 genomas completos de Wolbachia y se identificaron sistemas de defensa. Las estructuras de dGTPasas de Wolbachia, R. felis, S. putrefaciens y E. coli se predijeron con Protenix y se acoplaron con dGTP usando HADDOCK 2.4. Las interacciones se caracterizaron con PLIP, la afinidad con PRODIGY‑LIG y se realizó mutagénesis in silico en E. coli. Resultados: El sistema dGTPasa está presente en el 99% de las cepas con sistemas de defensa. La dGTPasa de Wolbachia mostró el mejor score (-30.2), una energía electrostática muy negativa (-128.1 kcal/mol) y una coordinación compacta del Mn²⁺ (cuadrado planar, distancias ≤2.44 Å) con tres puentes salinos. R. felis presentó un score similar (-29.2) pero menor componente electrostático (-44.9 kcal/mol). Las dGTPasas de vida libre (S. putrefaciens y E. coli) mostraron scores menos favorables (-22.3 y -21.5). La mutagénesis (Phe391→Tyr, Glu400→Met) en E. coli no reprodujo la alta afinidad de Wolbachia. Conclusión: La dGTPasa de Wolbachia sugiere tener una especialización estructural que la hace particularmente eficiente en la unión de dGTP, sugiriendo un papel en la depleción de dNTPs como un mecanismo antiviral.
Introdução: Wolbachia é um endossimbionte que protege seu hospedeiro contra infecções virais, embora os mecanismos subjacentes não sejam totalmente compreendidos. Este estudo in silico explora a presença de sistemas de defesa antiviral em Wolbachia, com ênfase em dGTPases, enzimas que degradam dGTP, um nucleotídeo essencial para a replicação viral. Metodologia: 194 genomas completos de Wolbachia foram analisados usando PADLOC e DefenseFinder, e os sistemas de defesa foram identificados. As dGTPases de Wolbachia, R. felis, Shewanella putrefaciens e Escherichia coli foram previstas usando Protenix e acopladas a dGTP usando HADDOCK 2.4. As interações foram caracterizadas com PLIP, a afinidade com PRODIGY LIG e a mutagênese in silico foi realizada em E. coli. Resultados: O sistema de dGTPases está presente em 99% das cepas com sistemas de defesa. A dGTPase da Wolbachia apresentou a melhor pontuação (-30,2), uma energia eletrostática muito negativa (-128,1 kcal/mol) e coordenação compacta de Mn²⁺ (planar quadrada, distâncias ≤2,44 Å) com três pontes salinas. A R. felis apresentou uma pontuação semelhante (-29,2), mas um componente eletrostático menor (-44,9 kcal/mol). As dGTPases de vida livre (S. putrefaciens e E. coli) apresentaram pontuações menos favoráveis (-22,3 e -21,5, respectivamente). A mutagênese (Phe391→Tyr, Glu400→Met) em E. coli não reproduziu a alta afinidade da Wolbachia. Conclusão: A dGTPase da Wolbachia sugere possuir uma especialização estrutural que a torna particularmente eficiente na ligação ao dGTP, indicando um papel na depleção de dNTPs como mecanismo antiviral.
Referencias
1. A.C. Pimentel, C.S. Cesar, M. Martins & R. Cogni. The antiviral effects of the symbiont bacteria Wolbachia in insects. Frontiers in Immunology, 11, 626329 (2021). https://doi.org/10.3389/fimmu. 2020.626329
2. M.J. Taylor, S.R. Bordenstein & B. Slatko. Microbe profile: Wolbachia: a sex selector, a viral pro-tector and a target to treat filarial nematodes. Microbiology (Reading), 164(11), 1345–1347 (2018). https://doi.org/10.1099/mic.0.000724
3. L. Teixeira, A. Ferreira & M. Ashburner. The bacterial symbiont Wolbachia induces resistance to RNA viral infections in Drosophila melanogaster. PLoS Biology, 6(12), e1000002 (2008). https://doi.org/ 10.1371/journal.pbio.1000002
4. M. Hussain, G. Zhang, M. Leitner, L.M. Hedges & S. Asgari. Wolbachia RNase HI contributes to virus blocking in the mosquito Aedes aegypti. iScience, 26(1), 105836 (2022). https://doi.org/10.1016/ j.isci.2022.105836
5. S.M. Rainey, J. Martinez, M. McFarlane, P. Juneja, P. Sarkies, A. Lulla, et al. Wolbachia blocks viral genome replication early in infection without a transcriptional response by the endosymbi-ont or host small RNA pathways. PLoS Pathogens, 12(4), e1005536. https://doi.org/10.1371/journal.ppat.1005536
6. L.A. Moreira, I. Iturbe-Ormaetxe, J.A. Jeffery, G. Lu, A.T. Pyke, L.M. Hedges, et al. A Wolbachia symbiont in Aedes aegypti limits infection with dengue, Chikungunya, and Plasmodi-um. Cell, 139(7), 1268–1278 (2009). https://doi.org/10.1016/j.cell.2009.11.042
7. G. Bian, Y. Xu, P. Lu, Y. Xie & Z. Xi. The endosymbiotic bacterium Wolbachia induces resistance to dengue virus in Aedes aegypti. PLoS Pathogens, 6(4), e1000833 (2010). https://doi.org/10.1371/journal.ppat.1000833
8. M. Leitner, C. Bishop & S. Asgari. Transcriptional response of Wolbachia to dengue virus infec-tion in cells of the mosquito Aedes aegypti. mSphere, 6(3), e0043321 (2021). Advance online publi-cation. https://doi.org/10.1128/mSphere.00433-21
9. F. Nainu, A. Trenerry & K.N. Johnson. Wolbachia-mediated antiviral protection is cell-autonomous. The Journal of General Virology, 100(11), 1587–1592 (2019). https://doi.org/10.1099/jgv.0.001342
10. V. Geoghegan, K. Stainton, S.M. Rainey, T.H. Ant, A.A. Dowle, T. Larson, et al. HIV-1 re-striction factor SAMHD1 is a deoxynucleoside triphosphate triphosphohydrolase. Na-ture, 480(7377), 379–382 (2011). https://doi.org/10.1038/nature10623
11. A.R.I. Lindsey, T. Bhattacharya, I.L.G. Newton & R.W. Hardy. Conflict in the intracellular lives of endosymbionts and viruses: A mechanistic look at Wolbachia-mediated pathogen-blocking. Vi-ruses, 10(4), 141 (2018). https://doi.org/10.3390/v10040141
12. F. Tesson, A. Hervé, E. Mordret, M. Touchon, C. d'Humières, J. Cury & A. Bernheim. Systemat-ic and quantitative view of the antiviral arsenal of prokaryotes. Nature Communications, 13(1), 2561 (2022). https://doi.org/10.1038/s41467-022-30269-9
13. L.J. Payne, T.C. Todeschini, Y. Wu, B.J. Perry, C.W. Ronson, P.C. Fineran, F.L. Nobrega & S.A. Jackson. Identification and classification of antiviral defence systems in bacteria and archaea with PADLOC reveals new system types. Nucleic Acids Research, 49(19), 10868–10878 (2021). https://doi.org/10.1093/nar/gkab883
14. M. Hauser, M. Steinegger & J. Söding. MMseqs software suite for fast and deep clustering and searching of large protein sequence sets. Bioinformatics (Oxford), 32(9), 1323–1330 (2016). https://doi.org/10.1093/bioinformatics/btw006
15. C.O. Barnes, Y. Wu, J. Song, G. Lin, E.L. Baxter, A.S. Brewster, et al. The crystal structure of dGTPase reveals the molecular basis of dGTP selectivity. Proceedings of the National Academy of Sciences of the United States of America, 116(19), 9333–9339 (2019). https://doi.org/10.1073/pnas.1814999116
16. PyMOL, 2020. URL: http://www.pymol.org/pymol
17. S. Kumar, G. Stecher, M. Suleski, M. Sanderford, S. Sharma & K. Tamura. MEGA12: Molecular Evolutionary Genetic Analysis Version 12 for Adaptive and Green Computing. Molecular Biology and Evolution, 41(12), msae263 (2024). https://doi.org/10.1093/molbev/msae263
18. C.-H. Lu, C.-C. Chen, C.-S. Yu, Y.-Y. Liu, J.-J. Liu, S.-T. Wei & Y.-F. Lin. MIB2: metal ion-binding site prediction and modeling server. Bioinformatics (Oxford), 38(18), 4428–4429 (2022). https://doi.org/10.1093/bioinformatics/btac534
19. E.F. Pettersen, T.D. Goddard, C.C. Huang, G.S. Couch, D.M. Greenblatt, E.C. Meng & T.E. Ferrin. UCSF Chimera--a visualization system for exploratory research and analysis. Journal of Computational Chemistry, 25(13), 1605–1612 (2004). https://doi.org/10.1002/jcc.20084
20. M.D. Hanwell, D.E. Curtis, D.C. Lonie, T. Vandermeersch, E. Zurek & G.R. Hutchison. Avo-gadro: an advanced semantic chemical editor, visualization, and analysis platform. Journal of Cheminformatics, 4(1), 17 (2012). https://doi.org/10.1186/1758-2946-4-17
21. Protenix Team, Y. Zhang, C. Gong, H. Zhang, W. Ma, Z. Liu, X. Chen, J. Guan, L. Wang & W. Xiao. Protenix v1: Toward high accuracy open source biomolecular structure prediction. bioRxiv: The Preprint Server for Biology, 1–13 (2026). https://doi.org/10.64898/2026.02.05.703733
22. R.V. Honorato, M.E. Trellet, B. Jiménez-García, J.J. Schaarschmidt, M. Giulini, V. Reys, et al. The HADDOCK2.4 web server for integrative modeling of biomolecular complexes. Nature Pro-tocols, 19(11), 3219–3241 (2024). https://doi.org/10.1038/s41596-024-01011-0
23. S. Salentin, S. Schreiber, V.J. Haupt, M.F. Adasme & M. Schroeder. PLIP: fully automated pro-tein-ligand interaction profiler. Nucleic Acids Research, 43(W1), W443–W447 (2015). https://doi.org/ 10.1093/nar/gkv315
24. A. Vangone, J. Schaarschmidt, P. Koukos, C. Geng, N. Citro, M.E. Trellet, L.C. Xue & A.M.J.J. Bonvin. Large-scale prediction of binding affinity in protein-small ligand complexes: the PROD-IGY-LIG web server. Bioinformatics (Oxford), 35(9), 1585–1587 (2019). https://doi.org/10.1093/bioinformatics/bty816
25. J.T. Marques & J.-L. Imler. The diversity of insect antiviral immunity: insights from viruses. Current Opinion in Microbiology, 32, 71–76 (2016). https://doi.org/10.1016/j.mib.2016.05.002
26. A. Bernheim & R. Sorek. The pan-immune system of bacteria: antiviral defence as a community resource. Nature Reviews: Microbiology, 18(2), 113–119 (2020). https://doi.org/10.1038/s41579-019-0278-2
27. H.G. Hampton, B.N.J. Watson & P.C. Fineran. The arms race between bacteria and their phage foes. Nature, 577(7790), 327–336 (2020). https://doi.org/10.1038/s41586-019-1894-8
28. A. Millman, S. Melamed, A. Leavitt, S. Doron, A. Bernheim, J. Hör, et al. An expanded arsenal of immune systems that protect bacteria from phages. Cell Host & Microbe, 30(11), 1556–1569.e5 (2022). https://doi.org/10.1016/j.chom.2022.09.017
29. T. Bhattacharya, I.L.G. Newton & R.W. Hardy. Viral RNA is a target for Wolbachia-mediated pathogen blocking. PLoS Pathogens, 16(6), e1008513 (2020). https://doi.org/10.1371/journal.ppat.1008513
30. N. Tal, A. Millman, A. Stokar-Avihail, T. Fedorenko, A. Leavitt, S. Melamed, et al. Bacteria deplete deoxynucleotides to defend against bacteriophage infection. Nature Microbiology, 7(8), 1200–1209 (2022). https://doi.org/10.1038/s41564-022-01158-0
31. D. Ayinde, N. Casartelli & O. Schwartz. Restricting HIV the SAMHD1 way: through nucleotide starvation. Nature Reviews: Microbiology, 10(10), 675–680 (2012). https://doi.org/10.1038/nrmicro2862
32. V. Geoghegan, K. Stainton, S.M. Rainey, T.H. Ant, A.A. Dowle, T. Larson, S. Hester, P.D. Charles, B. Thomas & S.P. Sinkins. Perturbed cholesterol and vesicular trafficking associated with dengue blocking in Wolbachia-infected Aedes aegypti cells. Nature Communications, 8(1), 526 (2017). https://doi.org/10.1038/s41467-017-00610-8
33. R. Cogni, S.D. Ding, A.C. Pimentel, J.P. Day & F.M. Jiggins. Wolbachia reduces virus infection in a natural population of Drosophila. Communications Biology, 4(1), 1327 (2021). https://doi.org/10.1038/ s42003-021-02838-z
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