Journal of Computer-Aided Molecular Design

, Volume 8, Issue 4, pp 367–388

Nucleotide-binding properties of adenylate kinase from Escherichia coli: A molecular dynamics study in aqueous and vacuum environments

  • Petra Kern
  • Roger M. Brunne
  • Gerd Folkers
Research Papers

Summary

The complex of adenylate kinase with its transition-state inhibitor has been studied by molecular dynamics simulations in water and in vacuum environments with the GROMOS force field over a period of 300 ps. The adenylate kinase, a member of the nucleotide-binding protein family, was exemplarily chosen for the inspection of the nucleotide-binding properties in the active site. The ligand binding and the domain movements have been studied in detail over the simulation period and compared with the crystal structure. Secondary structure transitions and domain closures defined those parts of the structure which are involved in an induced-fit movement of the enzyme. The presence of more stable hydrogen bonds on the substrate side leads to the assumption that substrate binding is more specific than cosubstrate binding. Reliable results were achieved only if water was explicitly included in the simulation.

Key words

GROMOS Domain movement Phosphate transfer 

Preview

Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.

References

  1. 1.
    Schulz, G.E., Curr. Opin. Struct. Biol., 2 (1992) 61.Google Scholar
  2. 2.
    Baker, P.J., Britton, K.L., Rice, D.W., Rob, A. and Stillman, T.J., J. Mol. Biol., 228 (1992) 662.Google Scholar
  3. 3.
    Elion, G.B., Furman, P.A., Fyfe, J.A., DeMiranda, P., Beauchamp, L. and Schaeffer, H.J., Proc. Natl. Acad. Sci. USA, 74 (1977) 5716.Google Scholar
  4. 4.
    Munch-Petersen, B. and Tyrsted, G., Leuk. Res., 12 (1988) 173.Google Scholar
  5. 5.
    Folkers, G., Trumpp-Kallmeyer, S., Gutbrod, O., Krickl, S., Fetzer, J. and Keil, G.M., J. Comput.-Aided Mol. Design, 5 (1991) 385.Google Scholar
  6. 6.
    Schulz, G.E., Schiltz, E., Tomaselli, A.G., Frank, R., Brune, M., Wittinghofer, A. and Schirmer, R.H., Eur. J. Biochem., 161 (1986) 127.Google Scholar
  7. 7.
    Diederichs, K. and Schulz, G.E., Biochemistry, 29 (1990) 8138.Google Scholar
  8. 8.
    Tsai, M.-D. and Yan, H., Biochemistry, 30 (1991) 6806.Google Scholar
  9. 9.
    Liang, P., Phillips Jr., G.N. and Glaser, M., Proteins, 9 (1991) 28.Google Scholar
  10. 10.
    Müller, C.W. and Schulz, G.E., J. Mol. Biol., 224 (1992) 159.Google Scholar
  11. 11.
    Saraste, M., Sibbald, P.R. and Wittinghofer, A., Trends Biochem. Sci., 15 (1990) 430.Google Scholar
  12. 12.
    Schulz, G.E., Müller, C.W. and Diederichs, K., J. Mol. Biol., 213 (1990) 627.Google Scholar
  13. 13.
    Holmes, R.K. and Singer, M.F., J. Biol. Chem., 248 (1973) 2014.Google Scholar
  14. 14.
    Van Gunsteren, W.F. and Berendsen, H.J.C., Groningen Molecular Simulation (GROMOS) Library Manual, Biomos, Groningen, 1987.Google Scholar
  15. 15.
    SYBYL 6.0, Tripos Associates, Inc., St. Louis, MO.Google Scholar
  16. 16.
    Berendsen, H.J.C., Grigera, J.R. and Straatsma, T.P., J. Phys. Chem., 91 (1987) 6269.Google Scholar
  17. 17.
    Ryckaert, J.P., Cicotti, G. and Berendsen, H.J.C., J. Comput. Phys., 23 (1977) 327.Google Scholar
  18. 18.
    Berendsen, H.J.C., Postma, J.P.M., Van Gunsteren, W.F., DiNola, A. and Haak, J.R., J. Chem. Phys., 81 (1984) 3684.Google Scholar
  19. 19.
    Levitt, M. and Sharon, R., Proc. Natl. Acad. Sci. USA, 85 (1988) 7557.Google Scholar
  20. 20.
    Harte, W.E., Swaminathan, S. and Beveridge, D.L., Proteins, 13 (1992) 175.Google Scholar
  21. 21.
    Foley, C.K., Pedersen, L.G., Charifson, P.S., Darden, T.A., Wittinghofer, A., Pai, E.F. and Anderson, M.W., Biochemistry, 31 (1992) 4951.Google Scholar
  22. 22.
    Kabsch, W. and Sander, C., Biopolymers, 22 (1983) 2577.Google Scholar
  23. 23.
    Schulz, G.E., Curr. Opin. Struct. Biol., 2 (1992) 61.Google Scholar
  24. 24.
    Gerstein, M., Schulz, G. and Chotia, C., J. Mol. Biol., 229 (1993) 494.Google Scholar
  25. 25.
    Saint-Girons, I., Gilles, A., Margarita, D., Michelson, S., Monnot, M., Fermandjian, S., Danchin, A. and Barzu, O., J. Biol. Chem., 262 (1987) 622.Google Scholar
  26. 26.
    Schulz, G.E., Müller, C.W. and Diederichs, K., J. Mol. Biol., 213 (1990) 627.Google Scholar
  27. 27.
    Reinstein, J., Schlichting, I. and Wittinghofer, A., Biochemistry, 29 (1990) 7451.Google Scholar
  28. 28.
    Pai, E.F., Krengel, U., Petsko, G.A., Goody, R.S., Kabsch, W. and Wittinghofer, A., EMBO J., 9 (1990) 2351.Google Scholar
  29. 29.
    Kjeldgaard, M. and Nyborg, J., J. Mol. Biol., 223 (1992) 721.Google Scholar
  30. 30.
    Story, R.M. and Steitz, T.A., Nature, 355 (1992) 374.Google Scholar
  31. 31.
    Shirakihara, Y. and Evans, P.R., J. Mol. Biol., 204 (1988) 973.Google Scholar
  32. 32.
    Goodford, P.J., J. Med. Chem., 28 (1985) 849.Google Scholar

Copyright information

© ESCOM Science Publishers B.V 1994

Authors and Affiliations

  • Petra Kern
    • 1
  • Roger M. Brunne
    • 2
  • Gerd Folkers
    • 1
  1. 1.Department of PharmacyETHZürichSwitzerland
  2. 2.Department of Physical ChemistryETH-HönggerbergZürichSwitzerland
  3. 3.Bayer AG, Pharma Research CentreWuppertalGermany

Personalised recommendations