Skip to main content
Log in

Computational design of d-peptide inhibitors of hepatitis delta antigen dimerization

Journal of Computer-Aided Molecular Design Aims and scope Submit manuscript

    We’re sorry, something doesn't seem to be working properly.

    Please try refreshing the page. If that doesn't work, please contact support so we can address the problem.

Abstract

Hepatitis delta virus (HDV) encodes a single polypeptide called hepatitis delta antigen (DAg). Dimerization of DAg is required for viral replication. The structure of the dimerization region, residues 12 to 60, consists of an anti-parallel coiled coil [Zuccola et al., Structure, 6 (1998) 821]. Multiple Copy Simultaneous Searches (MCSS) of the hydrophobic core region formed by the bend in the helix of one monomer of this structure were carried out for many diverse functional groups. Six critical interaction sites were identified. The Protein Data Bank was searched for backbone templates to use in the subsequent design process by matching to these sites. A 14 residue helix expected to bind to the d-isomer of the target structure was selected as the template. Over 200 000 mutant sequences of this peptide were generated based on the MCSS results. A secondary structure prediction algorithm was used to screen all sequences, and in general only those that were predicted to be highly helical were retained. Approximately 100 of these 14-mers were model built as d-peptides and docked with the l-isomer of the target monomer. Based on calculated interaction energies, predicted helicity, and intrahelical salt bridge patterns, a small number of peptides were selected as the most promising candidates. The ligand design approach presented here is the computational analogue of mirror image phage display. The results have been used to characterize the interactions responsible for formation of this model anti-parallel coiled coil and to suggest potential ligands to disrupt it.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

References

  1. Fields, B.N., Knipe, D.M. and Howley, P.M. (Eds.), Fields Virology, 3rd ed., Lippincott-Raven Publishers, Philadelphia, PA, 1996.

    Google Scholar 

  2. Xia, Y. and Lai, M.M.C., J. Virol., 66 (1992) 6641.

    Google Scholar 

  3. Wang, J. and Lemon, S., J. Virol., 67 (1993) 446.

    Google Scholar 

  4. Zuccola, H., Lemon, S., Erickson, B. and Hogle, J.M., Structure, 6 (1998) 821.

    Google Scholar 

  5. Chao, M., Hsieh, S.Y. and Taylor, J., J. Virol., 64 (1990) 5066.

    Google Scholar 

  6. Rozzelle, J., Wang, J., Wagner, D., Erickson, B. and Lemon, S., Proc. Natl. Acad. Sci. USA, 92 (1995) 382.

    Google Scholar 

  7. Wild, C., Oas, T., McDanal, C., Bolognesi, D. and Matthews, T., Proc. Natl. Acad. Sci. USA, 89 (1992) 10537.

    Google Scholar 

  8. Wild, C., Shugars, D., Greenwell, T., McDanal, C. and Matthews, T., Proc. Natl. Acad. Sci. USA, 91 (1994) 9770.

    Google Scholar 

  9. Chen, C., Matthew, T., McDanal, C., Bolognesi, D. and Greenberg, M., J. Virol., 69 (1995) 3771.

    Google Scholar 

  10. Milton, R., Milton, S. and Kent, S., Science, 256 (1993) 1445.

    Google Scholar 

  11. Guichard, G., Benkirane, N., Zeder-Lutz, G., Van Regenmortel, M., Briand, J. and Muller, S., Proc. Natl. Acad. Sci. USA, 91 (1994) 9765.

    Google Scholar 

  12. Schumacher, T., Mayr, L., Minor, D., Milhollen, M., Burgess, M. and Kim, P., Science, 271 (1996) 1854.

    Google Scholar 

  13. Miranker, A. and Karplus, M., Proteins, 11 (1991) 29.

    Google Scholar 

  14. Evensen, E., Joseph-McCarthy, D. and Karplus, M., MCSS version 2.1 (1997)

  15. Chandonia, J. and Karplus, M., Secondary structure/class prediction program (1997)

  16. Brooks, B.R., Bruccoleri, R.E., Olafson, B.D., States, D.J., Swaminathan, S. and Karplus, M., J. Comput. Chem., 4 (1983) 187.

    Google Scholar 

  17. MacKerell, A.D., Bashford, D., Bellott, M., Dunbrack, R.L., Evanseck, J.D., Field, M.J., Fischer, S., Gao, J., Guo, H., Ha, S., Joseph-McCarthy, D., Kuchnir, L., Kuczera, K., Lau, F.T.K., Mattos, C., Michnick, S., Ngo, T., Nguyen, D.T., Prodhom, B., Reiher, W.E., Roux, B., Schlenkrich, M., Smith, J.C., Stote, R., Straub, J., Watanabe, M., Wiorkiewicz-Kuczera, J., Yin, D. and Karplus, M., J. Phys. Chem. B, 102 (1998) 3586.

    Google Scholar 

  18. Neria, E., Fischer, S. and Karplus, M., J. Chem. Phys., 105 (1996) 1902.

    Google Scholar 

  19. Caflisch, A., Miranker, A. and Karplus, M., J. Med. Chem., 36 (1993) 2142.

    Google Scholar 

  20. Eisen, M., Wiley, D., Karplus, M. and Hubbard, R., Proteins, 19 (1994) 199.

    Google Scholar 

  21. Miranker, A. and Karplus, M., Proteins, 23 (1995) 472.

    Google Scholar 

  22. Quanta, MSI (1992).

  23. Hogrefe, H., Griffith, J., Rossman, M. and Goldberg, E., J. Biol. Chem., 262 (1987) 13155.

    Google Scholar 

  24. Ponder, J.W and Richards, F.M., J. Mol. Biol., 193 (1987) 775.

    Google Scholar 

  25. Xiong, H., Buckwalter, B.L., Shieh, H.-M. and Hecht, M.H., Proc. Natl. Acad. Sci. USA, 92 (1995) 6349.

    Google Scholar 

  26. Marqusee, S. and Baldwin, R., Proc. Natl. Acad. Sci. USA, 84 (1987) 8898.

    Google Scholar 

  27. Sindelar, C., Hendsch, Z. and Tidor, B., Protein Sci., 7 (1998) 1898.

    Google Scholar 

  28. Chou, P. and Fasman, G., Biochemistry, 13 (1974) 211.

    Google Scholar 

  29. Chandonia, J.M. and Karplus, M., Protein Sci., 4 (1995) 275.

    Google Scholar 

  30. Grootenhuis, P.D.J. and Van Helden, S.P., Comput. Approaches Supramol. Chem., (1994) 137.

  31. Grootenhuis, P.D.J. and van Galen, P.J.M., Acta Crystallogr., D51 (1995) 560.

    Google Scholar 

  32. Holloway, M.K., Wai, J.M., Halgren, T.A., Fitzgerald, P.M.D., Vacca, J.P., Dorsey, B.D., Levin, R.B., Thompson, W.J., Chen, L.J., deSolms, S.J., Gaffin, N., Ghosh, A.K., Giuliani, E.A., Graham, S.L., Guare, J.P., Hungate, R.W., Lyle, T.A., Sanders, W.M., Tucker, T.J., Wiggins, M., Wiscount, C.M., Woltersdorf, O.W., Young, S.D., Darke, P.L. and Zugay, J.A., J. Med. Chem., 38 (1995) 305.

    Google Scholar 

  33. Joseph-McCarthy, D., Hogle, J.M. and Karplus, M., Proteins, 29 (1997) 32.

    Google Scholar 

  34. Kurinov, I.V. and Harrison, R.W., Nat. Struct. Biol., 1 (1994) 735.

    Google Scholar 

  35. Caflisch, A. and Karplus, M., Perspect. Drug Discov. Design, 3 (1995) 51.

    Google Scholar 

Download references

Author information

Authors and Affiliations

Authors

Rights and permissions

Reprints and permissions

About this article

Cite this article

Elkin, C.D., Zuccola, H.J., Hogle, J.M. et al. Computational design of d-peptide inhibitors of hepatitis delta antigen dimerization. J Comput Aided Mol Des 14, 705–718 (2000). https://doi.org/10.1023/A:1008146015629

Download citation

  • Issue Date:

  • DOI: https://doi.org/10.1023/A:1008146015629

Navigation