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Dynamics and binding interactions of peptide inhibitors of dengue virus entry

  • Diyana Mohd Isa
  • Sek Peng Chin
  • Wei Lim Chong
  • Sharifuddin M. Zain
  • Noorsaadah Abd Rahman
  • Vannajan Sanghiran LeeEmail author
Original Paper

Abstract

In this study, we investigate the binding interactions of two synthetic antiviral peptides (DET2 and DET4) on type II dengue virus (DENV2) envelope protein domain III. These two antiviral peptides are designed based on the domain III of the DENV2 envelope protein, which has shown significant inhibition activity in previous studies and can be potentially modified further to be active against all dengue strains. Molecular docking was performed using AutoDock Vina and the best-ranked peptide-domain III complex was further explored using molecular dynamics simulations. Molecular mechanics-Poisson–Boltzmann surface area (MM-PBSA) was used to calculate the relative binding free energies and to locate the key residues of peptide–protein interactions. The predicted binding affinity correlated well with the previous experimental studies. DET4 outperformed DET2 and is oriented within the binding site through favorable vdW and electrostatic interactions. Pairwise residue decomposition analysis has revealed several key residues that contribute to the binding of these peptides. Residues in DET2 interact relatively lesser with the domain III compared to DET4. Dynamic cross-correlation analysis showed that both the DET2 and DET4 trigger different dynamic patterns on the domain III. Correlated motions were seen between the residue pairs of DET4 and the binding site while binding of DET2 results in anti-correlated motion on the binding site. This work showcases the use of computational study in elucidating and explaining the experiment observation on an atomic level.

Keywords

DENV2 Antiviral peptides Molecular dynamics simulations Molecular docking 

Notes

Acknowledgements

The authors thank Hadieh Monajemi for her diligent proofreading of this paper. This research supported financially by Faculty Research Grant, University Malaya (GPF062B-2018).

Compliance with ethical standards

Conflict of interest

The authors declare no conflicts of interest.

Supplementary material

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References

  1. 1.
    Seema, Jain, S.K.: Molecular mechanism of pathogenesis of dengue virus: entry and fusion with target cell. Indian J. Clin. Biochem. 20, 92–103 (2005)CrossRefGoogle Scholar
  2. 2.
    Parikesit, A.A., Kinanty, Tambunan, U.S.F.: Screening of commercial cyclic peptides as inhibitor envelope protein dengue virus (DENV) through molecular docking and molecular dynamics. Pak. J. Biol. Sci. 16, 1836–1848 (2013)CrossRefGoogle Scholar
  3. 3.
    Mustafa, L.C.M.S., Rasotgi, C.V., Jain, C.S., Gupta, L.C.V.: Discovery of fifth serotype of dengue virus (DENV-5): a new public health dilemma in dengue control. Med. J. Armed Forces India. 71, 67–70 (2015)CrossRefGoogle Scholar
  4. 4.
    Leitmeyer, K.C., Vaughn, D.W., Watts, D.M., Salas, R., Chacon, I.V.D., Ramos, C., Rico-Hesse, R.: Dengue virus structural differences that correlate with pathogenesis. J. Virol. 89, 4738–4747 (1999)Google Scholar
  5. 5.
    Modis, Y., Ogata, S., Clements, D., Harrison, S.C.: Structure of the dengue virus envelope protein after membrane fusion. Nature 427, 313–319 (2004)CrossRefADSGoogle Scholar
  6. 6.
    van der Schaar, H.M., Rust, M.J., Waarts, B.-L., Van der Ende-Metselaar, H., Kuhn, R.J., Wilschut, J., Zhuang, X., Smit, J.M.: Characterization of the early events in dengue virus cell entry by biochemical assays and single-virus tracking. J. Virol. 81, 12019–12028 (2007)Google Scholar
  7. 7.
    Zhang, Y., Zhang, W., Ogata, S., Clements, D., Strauss, J.H., Baker, T.S., Kuhn, R.J., Rossmann, M.G.: Conformational changes of the flavivirus E glycoprotein. Structure 12, 1607–1618 (2004)CrossRefGoogle Scholar
  8. 8.
    Modis, Y., Ogata, S., Clements, D., Harisson, S.C.: Variable surface epitopes in the crystal structure of dengue virus type 3 envelope glycoprotein. J. Virol. 79(2), 1223–1231 (2005)CrossRefGoogle Scholar
  9. 9.
    Pierson, T.C., Diamond, M.S.: Molecular mechanisms of antibody-mediated neutralisation of flavivirus infection. Expert Rev. Mol. Med. 10, e12 (2008)CrossRefGoogle Scholar
  10. 10.
    Crill, W.D., Roehrig, J.T.: Monoclonal antibodies that bind to domain III of dengue virus E glycoprotein are the most efficient blockers of virus adsorption to Vero cells. J. Virol. 75(16), 7769–7773 (2001)CrossRefGoogle Scholar
  11. 11.
    Hung, J.J., Hsieh, M.T., Young, M.J., Kao, C.L., King, C.C., Chang, W.: An external loop region of domain III of dengue virus type 2 envelope protein is involved in serotype-specific binding to mosquito but not mammalian cells. J. Virol. 78, 378–388 (2004)CrossRefGoogle Scholar
  12. 12.
    Chen, Y., Maguire, T., Hileman, R.E., Fromm, J.R., Esko, J.D., Linhardt, R.J., Marks, R.M.: Dengue virus infectivity depends on envelope protein binding to target cell heparan sulfate. Nat. Med. 3, 866–871 (1997)CrossRefGoogle Scholar
  13. 13.
    Chiu, M.W., Yang, Y.L.: Blocking the dengue virus 2 infections on BHK-21 cells with purified recombinant dengue virus 2 E protein expressed in Escherichia coli. Biochem. Biophys. Res. Commun. 309, 672–678 (2003)CrossRefGoogle Scholar
  14. 14.
    Rey, F.A., Heinz, F.X., Mandl, C., Kunz, C., Harrison, S.C.: The envelope glycoprotein from tick-borne encephalitis virus at 2 Å resolution. Nature 375, 291–298 (1995)CrossRefADSGoogle Scholar
  15. 15.
    Otvos, L., Wade, J.D.: Current challenges in peptide-based drug discovery. Front. Chem. 2, 62 (2014)Google Scholar
  16. 16.
    Röckendorf, N., Borschbach, M., Frey, A.: Molecular evolution of peptide ligands with custom-tailored characteristics for targeting of glycostructures. PLoS Comput. Biol. 8, 1–10 (2012)CrossRefGoogle Scholar
  17. 17.
    Hancock, R.E.W., Lehrer, R.: Cationic peptides: a new source of antibiotics. Trends Biotechnol. 16, 82–88 (1998)CrossRefGoogle Scholar
  18. 18.
    Yin, Z., Patel, S.J., Wang, W.-L., Wang, G., Chan, W.-L., Rao, K.R.R., Alam, J., Jeyaraj, D.A., Ngew, X., Patel, V., Beer, D., Lim, S.P., Vasudevan, S.G., Keller, T.H.: Peptide inhibitors of dengue virus NS3 protease. Part 1: warhead. Bioorganic med. Chem. Lett. 16, 36–39 (2006)CrossRefGoogle Scholar
  19. 19.
    Prusis, P., Junaid, M., Petrovska, R., Yahorava, S., Yahorau, A., Katzenmeier, G., Lapins, M., Wikberg, J.E.S.: Design and evaluation of substrate-based octapeptide and non substrate-based tetrapeptide inhibitors of dengue virus NS2B–NS3 proteases. Biochem. Biophys. Res. Commun. 434, 767–772 (2013)CrossRefGoogle Scholar
  20. 20.
    Clum, S., Ebner, K., Padmanabhan, R.: Cotranslational membrane insertion of the serine proteinase precursor NS2B-NS3 (pro) of dengue virus. J. Biol. Chem. 272, 30715–30723 (1997)CrossRefGoogle Scholar
  21. 21.
    Falgout, B., Miller, R.H., Lai, C.J.: Deletion analysis of dengue virus type 4 nonstructural protein NS2B: identification of a domain required for NS2B-NS3 protease activity. J. Virol. 67, 2034–2042 (1993)Google Scholar
  22. 22.
    Falgout, B., Pethel, M., Zhang, Y.M., Lai, C.J.: Both nonstructural proteins NS2B and NS3 are required for the proteolytic processing of dengue virus nonstructural proteins. J. Virol. 65, 2467–2475 (1991)Google Scholar
  23. 23.
    Zhang, L., Mohan, P.M., Padmanabhan, R.: Processing and localization of dengue virus type 2 polyprotein precursor NS3-NS4A-NS4B-NS5. J. Virol. 66, 7549–7554 (1992)Google Scholar
  24. 24.
    Schmidt, A.G., Yang, P.L., Harrison, S.C.: Peptide inhibitors of dengue-virus entry target a late-stage fusion intermediate. PLoS Pathog. 6, e1000851 (2010)CrossRefGoogle Scholar
  25. 25.
    Schmidt, A.G., Yang, P.L., Harrison, S.C.: Peptide inhibitors of flavivirus entry derived from the E protein stem. J. Virol. 84, 12549–12554 (2010)CrossRefGoogle Scholar
  26. 26.
    Costin, J.M., Jenwitheesuk, E., Lok, S.-M., Hunsperger, E., Conrads, K.A., Fontaine, K.A., Rees, C.R., Rossmann, M.G., Isern, S., Samudrala, R., Michael, S.F.: Structural optimization and de novo design of dengue virus entry inhibitory peptides. PLoS Negl. Trop. Dis. 4, e721 (2010)CrossRefGoogle Scholar
  27. 27.
    Hrobowski, Y.M., Garry, R.F., Michael, S.F.: Peptide inhibitors of dengue virus and West Nile virus infectivity. J. Virol. 2, 49 (2005)CrossRefGoogle Scholar
  28. 28.
    Xu, Y., Rahman, N.A., Othman, R., Hu, P., Huang, M.: Computational identification of self-inhibitory peptides from envelope proteins. Proteins 80, 2154–2168 (2012)CrossRefGoogle Scholar
  29. 29.
    Panya, A., Sawasdee, N., Junking, M., Srisawat, C., Choowongkomon, K., Yenchitsomanus, P.T.: A peptide inhibitor derived from the conserved ectodomain region of DENV membrane (M) protein with activity against dengue virus infection. Chem. Biol. Drug Des. 86, 1093–1104 (2015)CrossRefGoogle Scholar
  30. 30.
    Lok, S.M., Costin, J.M., Hrobowski, Y.M., Hoffmann, A.R., Rowe, D.K., Kukkaro, P., Holdaway, H., Chipman, P., Fontaine, K.A., Holbrook, M.R., Garry, R.F., Kostyuchenko, V., Wimley, W.C., Isern, S., Rossmann, M.G., Michael, S.F.: Release of dengue virus genome induced by a peptide inhibitor. PLoS One 7, e50995 (2012)CrossRefADSGoogle Scholar
  31. 31.
    Lalezari, J.P., Henry, K., O’Hearn, M., Montaner, J.S., Piliero, P.J., Trottier, B., Walmsley, S., Cohen, C., Kuritzkes, D.R., Eron Jr., J.J., Chung, J., DeMasi, R., Donatacci, L., Drobnes, C., Delehanty, J., Salgo, M.: Enfuvirtide, an HIV-1 fusion inhibitor, for drug-resistant HIV infection in North and South America. N. Engl. J. Med. 348, 2175–2185 (2003)CrossRefGoogle Scholar
  32. 32.
    Champagne, K., Shishido, A., Root, M.J.: Interactions of HIV-1 inhibitory peptide T20 with the gp41 N-HR coiled coil. J. Biol. Chem. 284, 3619–3627 (2009)CrossRefGoogle Scholar
  33. 33.
    Wild, C., Oas, T., McDanal, C., Bolognesi, D., Matthews, T.: A synthetic peptide inhibitor of human immunodeficiency virus replication: correlation between solution structure and viral inhibition. Proc. Natl. Acad. Sci. U. S. A. 89, 10537–10541 (1992)CrossRefADSGoogle Scholar
  34. 34.
    Kilby, J.M., Hopkins, S., Venetta, T.M., DiMassimo, B., Cloud, G.A., Lee, J.Y., Alldredge, L., Hunter, E., Lambert, D., Bolognesi, D., Matthews, T., Johnson, M.R., Nowak, M.A., Shaw, G.M., Saag, M.S.: Potent suppression of HIV-1 replication in humans by T-20, a peptide inhibitor of gp41-mediated virus entry. J. Nat. Med. 4, 1302–1307 (1998)CrossRefGoogle Scholar
  35. 35.
    Chan, D.C., Kim, P.S.: HIV entry and its inhibition. Cell 93, 681–684 (1998)CrossRefGoogle Scholar
  36. 36.
    Alhoot, M.A., Rathinam, A.K., Wang, S.M., Manikam, R., Sekaran, S.D.: Inhibition of dengue virus entry into target cells using synthetic antiviral peptides. Int. J. Med. Sci. 10, 719–729 (2013)CrossRefGoogle Scholar
  37. 37.
    Mazumder, R., Hu, Z.Z., Vinayaka, C.R., Sagripanti, J.L., Frost, S.D.W., Kosakovsky Pond, S.L., Wu, C.H.: Computational analysis and identification of amino acid sites in dengue E proteins relevant to development of diagnostics and vaccines. Virus Genes 35, 175–186 (2007)CrossRefGoogle Scholar
  38. 38.
    Erb, S.M., Butrapet, S., Moss, K.J., Luy, B.E., Childers, T., Calvert, A.E., Silengo, S.J., Roehrig, J.T., Huang, C.Y., Blair, C.D.: Domain-III FG loop of the dengue virus type 2 envelope protein is important for infection of mammalian cells and Aedes aegypti mosquitoes. J. Virol. 406, 328–335 (2010)CrossRefGoogle Scholar
  39. 39.
    Protein Data Bank (PDB). http://www.rcsb.org/pdb/ (2014). Accessed 20 January 2014
  40. 40.
    Volk, D.E., Lee, Y.-C., Li, X., Thiviyanathan, V., Gromowski, G.D., Li, L., Lamb, A.R., Beasley, D.W.C., Barrett, A.D., Gorenstein, D.G.: Solution structure of the envelope protein domain III of dengue-4 virus. J. Virol. 364, 147–154 (2007)CrossRefGoogle Scholar
  41. 41.
    Accelrys. Discovery Studio (version 2.5.5). San Diego, California. (2009)Google Scholar
  42. 42.
    Kaur, H., Garg, A., Raghava, G.P.S.: PEPstr: a de novo method for tertiary structure prediction of small bioactive peptides. Protein Pept. Lett. 14, 626–630 (2007)CrossRefGoogle Scholar
  43. 43.
    Trott, O., Olson, A.J.: AutoDock Vina: improving the speed and accuracy of docking with a new scoring function, efficient optimization and multithreading. J. Comput. Chem. 31, 455–461 (2010)Google Scholar
  44. 44.
    PepCalc.com. http://pepcalc.com/ (2015). Accessed 15 May 2015
  45. 45.
    Götz, A.W., Williamson, M.J., Xu, D., Poole, D., Grand, S.L., Walker, R.C.: Routine microsecond molecular dynamics simulations with AMBER - part I: generalized Born. J. Chem. Theory Comput. 8, 1542–1555 (2012)Google Scholar
  46. 46.
    Grand, S.L., Götz, A.W., Walker, R.C.: SPFP: speed without compromise—a mixed precision model for GPU accelerated molecular dynamics simulations. Comput. Phys. Commun. 184, 374–380 (2013)CrossRefADSGoogle Scholar
  47. 47.
    Salomon-Ferrer, R., Götz, A.W., Poole, D., Grand, S.L., Walker, R.C.: Routine microsecond molecular dynamics simulations with AMBER on GPUs. 2. Explicit solvent particle mesh Ewald. J. Chem. Theory Comput. 9, 3878–3888 (2013)CrossRefGoogle Scholar
  48. 48.
    Case, D.A., Darden, T.A., Cheatham, T.E.I.I.I., Simmerling, C.L., Wang, J., Duke, R.E., Luo, R., Walker, R.C., Zhang, W., Merz, K.M., Roberts, B., Hayik, S., Roitberg, A., Seabra, G., Swails, J., Goetz, A.W., Kolossváry, I., Wong, K.F., Paesani, F., Vanicek, J., Wolf, R.M., Liu, J., Wu, X., Brozell, S.R., Steinbrecher, T., Gohlke, H., Cai, Q., Ye, X., Wang, J., Hsieh, M.J., Cui, G., Roe, D.R., Mathews, D.H., Seetin, M.G., Salomon-Ferrer, R., Sagui, C., Babin, V., Luchko, T., Gusarov, S., Kovalenko, A., Kollman, P.A.: Amber 12. University of California, San Francisco (2012)Google Scholar
  49. 49.
    Weber, W., Hünenberger, P., McCammon, J.: Molecular dynamics simulations of a polyalanine octapeptide under Ewald boundary conditions: influence of artificial periodicity on peptide conformation. J. Phys. Chem. B104, 3668–4575 (2000)CrossRefGoogle Scholar
  50. 50.
    Darden, T., York, D., Pedersen, L.: Particle mesh Ewald: an N log (N) method for Ewald sums in large systems. J. Chem. Phys. 98, 10089–10092 (1993)CrossRefADSGoogle Scholar
  51. 51.
    Essmann, U., Perera, L., Berkowitz, M.L., Darden, T., Lee, H., Pedersen, L.: A smooth particle meshes Ewald potential. J. Chem. Phys. 103, 8577–8592 (1995)CrossRefADSGoogle Scholar
  52. 52.
    Roe, D.R., Cheatham, T.E.: PTRAJ and CPPTRAJ: software for processing and analysis of molecular dynamics trajectory data. J. Chem. Theory Comput. 9, 3084–3095 (2013)CrossRefGoogle Scholar
  53. 53.
    Kollman, P.A., Massova, I., Reyes, C., Kuhn, B., Huo, S., Chong, L., Lee, M., Lee, T., Duan, Y., Wang, W., Donini, O., Cieplak, P., Srinivasan, J., Case, D.A., Cheatham, T.E.: Calculating structures and free energies of complex molecules: combining molecular mechanics and continuum models. Acc. Chem. Res. 33, 889–897 (2000)CrossRefGoogle Scholar
  54. 54.
    Schrödinger: The PyMOL Molecular Graphics System (Version 1.6). LLC, New York (2015)Google Scholar
  55. 55.
    Law, R.J., Capener, C., Baaden, M., Bond, P.J., Campbell, J., Patargias, G., Arinaminpathy, Y., Sansom, M.S.P.: Membrane protein structure quality in molecular dynamics simulations. J. Mol. Graph. Model. 157–165 (2005)Google Scholar
  56. 56.
    Knapp, B., Frantal, S., Cibena, M., Schreiner, W., Bauer, P.: Is an intuitive convergence definition of molecular dynamics simulations solely based on the root mean square deviation possible? J. Comput. Biol. 18, 997–1005 (2011)MathSciNetCrossRefGoogle Scholar
  57. 57.
    Król, M., Roterman, I., Spólnik, P.: Analysis of correlated domain motions in IgG light chain reveals possible mechanisms of immunological signal transduction. Proteins 59, 545–554 (2005)CrossRefGoogle Scholar
  58. 58.
    Sousa, S.F., Fernandes, P.A., Ramos, M.J.: Molecular dynamics simulations on the critical states of the farnesyltransferase enzyme. Bioorganic Med. Chem. 17, 3369–3378 (2009)CrossRefGoogle Scholar
  59. 59.
    Yin, J., Bowen, D., Southerland, W.M.: Barnase thermal titration via molecular dynamics simulations: detection of early denaturation sites. J. Mol. Graph. Model. 24, 233–243 (2006)CrossRefGoogle Scholar

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© Springer Nature B.V. 2019

Authors and Affiliations

  1. 1.Department of Chemistry, Faculty of ScienceUniversity of MalayaKuala LumpurMalaysia

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