Russian Journal of Bioorganic Chemistry

, Volume 29, Issue 6, pp 523–533 | Cite as

Interaction of Cardiotoxin A5 with Membrane: Role of Conformational Heterogeneity and Hydrophobic Properties

  • A. G. Konshina
  • P. E. Volynsky
  • A. S. Arseniev
  • R. G. Efremov
Article

Abstract

The hypothesis that local conformational differences of the snake venom cardiotoxins (cytotoxins, CT) may play a significant role in their interaction with membrane was tested by molecular modeling of the behavior of the CT A5 from the venom of Naja atra in water and at the water–membrane interface. Two models of the CT A5 spatial structure are known: the first was obtained by X-ray analysis and the second, by NMR studies in solution. A molecular dynamics (MD) analysis demonstrated that loop II of the toxin has a fixed Ω-like shape in water, which does not depend on its initial structure. An interaction of the experimentally derived (X-ray and NMR) conformations and MD simulated conformations of CT A5 with the lipid bilayer was studied by the Monte Carlo method using the previously developed model of the implicit membrane. It is found that: (1) unlike the previously studied CT2 from the venom of cobra Naja oxiana, CT A5 has only loops I and II bound to the membrane with the involvement of a lesser number of hydrophobic residues. (2) A long hydrophobic area is formed on the surface of CT A5 due to the Ω-like shape of loop II and the arrangement of loop I in proximity to loop II. This hydrophobic area favors the toxin embedding into the lipid bilayer. (3) The toxin retains its conformation upon interaction with the membrane. (4) The CT A5 molecule has close values of the potential energy in the membrane and in aqueous environment, which suggests dynamic character of the binding. The results of the molecular modeling indicate a definite configuration of loops I and II and, consequently, a specific character of distribution of polar and apolar properties on the toxin surface, which turns out to be the most energetically favorable.

conformational search molecular dynamics molecular modeling Monte Carlo method protein solvation model 

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References

  1. 1.
    Kumar, T., Jayaraman, G., Lee, C., Arunkumar, A., Sivaraman, T., Samuel, D., and Yu, C., J. Biomol. Struct. and Dyn., 1997, vol. 15, pp. 431–463.Google Scholar
  2. 2.
    Fletcher, J.E., Hubert, M., Wieland, S.J., Gong, Q.H., and Jiang, M.S., Toxicon, 1996, vol. 34, pp. 1301–1311.Google Scholar
  3. 3.
    Chiou, S.H., Hung, C.C., Huang, H.C., Chen, S.T., Wang, K.T., and Yang, C.C., Biochem. Biophys. Res. Commun., 1995, vol. 206, pp. 22–32.Google Scholar
  4. 4.
    Bilwes, A., Rees, B., Moras, D., Menez, R., and Menez, A., J. Mol. Biol., 1994, vol. 239, pp. 122–136.Google Scholar
  5. 5.
    Aripov, T.F., Gasanov, S.E., Salakhutdinov, B.A., Rozenshtein, A., and Kamaev, F.G., Gen. Physiol. Biophys., 1989, vol. 8, pp. 459–474.Google Scholar
  6. 6.
    Chien, K.-Y., Chiang, C.-M., Hseu, Y.-C., Vyas, A., Gordon, S., and Wu, W.-G., J. Biol. Chem., 1994, vol. 269, pp. 14 473–14 483.Google Scholar
  7. 7.
    Desormeaux, A., Laroche, G., Bougis, P.E., and Pezolet, M., Biochemistry, 1992, vol. 31, pp. 12 173–12 182.Google Scholar
  8. 8.
    Dubovskii, P.V., Dementieva, D.V., Bocharov, E.V., Utkin, Yu.N., and Arseniev, A.S., J. Mol. Biol., 2001, vol. 305, pp. 137–149.Google Scholar
  9. 9.
    Dementieva, D.V., Bocharov, E.V., and Arseniev, A.S., Eur. J. Biochem., 1999, vol. 263, pp. 152–162.Google Scholar
  10. 10.
    White, S.H. and Wimley, W.C., Annu. Rev. Biophys. Biomol. Struct., 1999, vol. 28, pp. 319–365.Google Scholar
  11. 11.
    Shai, Y., Biochim. Biophys. Acta, 1999, vol. 1462, pp. 55–70.Google Scholar
  12. 12.
    Forrest, L.R. and Sansom, M.S., Curr. Opin. Struct. Biol., 2000, vol. 10, pp. 174–181.Google Scholar
  13. 13.
    Woolf, T.B. and Roux, B., Proteins, 1996, vol. 24, pp. 92–114.Google Scholar
  14. 14.
    Tieleman, D.P. and Berendsen, H.J.C., Biophys. J., 1998, vol. 74, pp. 2786–2801.Google Scholar
  15. 15.
    Woolf, T.B., Biophys. J., 1998, vol. 74, pp. 115–131.Google Scholar
  16. 16.
    Zhou, F. and Schulten, K., Proteins: Struct. Funct. Genet., 1996, vol. 25, pp. 12–27.Google Scholar
  17. 17.
    Efremov, R.G., Nolde, D.E., Volynsky, P.E., Chernyavsky, A.A., Dubovskii, P.V., and Arseniev, A.S., FEBS Lett., 1999, vol. 462, pp. 205–210.Google Scholar
  18. 18.
    Tieleman, D.P. and Berendsen, H.J.C., J. Chem. Phys., 1996, vol. 105, pp. 4871–4880.Google Scholar
  19. 19.
    Efremov, R.G., Nolde, D.E., Vergoten, G., and Arseniev, A.S., Biophys. J., 1999, vol. 76, pp. 2460–2471.Google Scholar
  20. 20.
    Nolde, D.E., Arseniev, A.S., Vergoten, G., and Efremov, R.G., J. Biomol. Struct. Dyn., 1997, vol. 15, pp. 1–18.Google Scholar
  21. 21.
    Nol'de, D.E., Volynskii, P.E., Arsen'ev, A.S., and Efremov, R.G., Bioorg. Khim., 2000, vol. 26, pp. 131–142.Google Scholar
  22. 22.
    Efremov, R.G., Volynsky, P.E., Nolde, D.E., Dubovskii, P.V., and Arseniev, A.S., Biophys. J., 2002, vol. 83, pp. 144–153.Google Scholar
  23. 23.
    Sun, Y.-J., Wu, W.-g., Chiang C.-M., Hsin A.-Y., and Hsiao, C.-D., Biochemistry, 1997, vol. 36, pp. 2403–2413.Google Scholar
  24. 24.
    Singhal, A., Chien, K.-Y., Wu, W.-g., and Gordon, S., Biochemistry, 1993, vol. 32, pp. 8036–8045.Google Scholar
  25. 25.
    Dubinnyi, M.A., Dubovskii, P.V., Utkin, Yu.N., Simonova, T.N., Barsukov, L.I., and Arsen'ev, A.S., Bioorg. Khim., 2001, vol. 27, pp. 84–94.Google Scholar
  26. 26.
    von Freyberg, B. and Braun, W., J. Comput. Chem., 1991, vol. 12, pp. 1065–1076.Google Scholar
  27. 27.
    Berendsen, H.J.C., van der Spoel, D., and van Drunen, R., Comput. Phys. Commun., 1995, vol. 91, pp. 43–56.Google Scholar
  28. 28.
    Darden, T., York, D., and Pederson, L., J. Chem. Phys., 1993, vol. 98, p. 10 089.Google Scholar
  29. 29.
    Kabsch, W. and Sander, C., Biopolymers, 1983, vol. 22, pp. 2577–2637.Google Scholar
  30. 30.
    Hubbard, S.J. and Thornton, J.M., NACCESS, Computer Program, Department of Biochemistry and Molecular Biology, University College, London, 1993.Google Scholar
  31. 31.
    Metropolis, N., Rosenbluth, A.W., Teller, A.H., and Teller, E., J. Chem. Phys., 1953, vol. 21, pp. 1087–1092.Google Scholar
  32. 32.
    Efremov, R.G. and Vergoten, G., J. Phys. Chem., 1995, vol. 99, pp. 10 658–10 666.Google Scholar

Copyright information

© MAIK “Nauka/Interperiodica” 2003

Authors and Affiliations

  • A. G. Konshina
    • 1
  • P. E. Volynsky
    • 1
  • A. S. Arseniev
    • 1
  • R. G. Efremov
    • 1
  1. 1.Shemyakin–Ovchinnikov Institute of Bioorganic ChemistryRussian Academy of SciencesMoscowRussia

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