Deciphering common failures in molecular docking of ligand-protein complexes

Abstract

Common failures in predicting crystal structures of ligand-protein complexes are investigated for three ligand-protein systems by a combined thermodynamic and kinetic analysis of the binding energy landscapes. Misdocked predictions in ligand-protein docking are classified as `soft' and `hard' failures. While a soft failure arises when the search algorithm is unable to find the global energy minimum corresponding to the crystal structure, a hard failure results from a flaw of the energy function to qualify the crystal structure as the predicted lowest energy conformation in docking simulations. We find that neither the determination of a single structure with the lowest energy nor finding the most common binding mode is sufficient to predict crystal structures of the complexes, which belong to the category of hard failures. In a proposed hierarchical approach, structural similarity clustering of the conformations, generated from equilibrium simulations with the simplified energy function, is followed by energy refinement with the AMBER force field. This protocol, that involves a hierarchy of energy functions, resolves some common failures in ligand-protein docking and detects crystallographic binding modes that were not found during docking simulations.

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References

  1. 1.

    Kuntz, I.D., Science, 257 (1992) 1078.

    Google Scholar 

  2. 2.

    Shoichet, B.K., Stroud, R.M., Santi, D.V., Kuntz, I.D. and Perry, K.M., Science, 259 (1993) 1445.

    Google Scholar 

  3. 3.

    Shoichet, B.K., Leach, A.R. and Kuntz, I.D., Proteins Struct. Funct. Genet., 34 (1999) 4.

    Google Scholar 

  4. 4.

    Kuntz, I.D., Meng, E.C. and Shoichet, B.K., Acc. Chem. Res., 27 (1994) 117.

    Google Scholar 

  5. 5.

    Rosenfeld, R., Vajda, S. and DeLisi, C., Annu. Rev. Biophys. Biomol. Struct., 24 (1995) 677.

    Google Scholar 

  6. 6.

    Straatsma, T.P. and McCammon, J.A., Annu. Rev. Phys. Chem., 43 (1992) 407.

    Google Scholar 

  7. 7.

    Cherfils, J. and Janin, J., Curr. Opin. Struct. Biol., 3 (1993) 265.

    Google Scholar 

  8. 8.

    Kollman, P., Chem. Rev., 93 (1993) 2395.

    Google Scholar 

  9. 9.

    Ajay and Murcko, M.A., J. Med. Chem., 38 (1995) 4953.

    Google Scholar 

  10. 10.

    Jones, G. and Willett, P., Curr. Opin. Biotechnol., 6 (1995) 652.

    Google Scholar 

  11. 11.

    Gschwend, D.A., Good, A.C. and Kuntz, I.D., J. Mol. Recognit., 9 (1996) 175.

    Google Scholar 

  12. 12.

    Shoichet, B.K. and Kuntz, I.D., J. Mol. Biol., 221 (1991) 327.

    Google Scholar 

  13. 13.

    Walls, P.H. and Sternberg, M.J.E., J. Mol. Biol., 228 (1992) 277.

    Google Scholar 

  14. 14.

    Vakser, I.A. and Aflalo, C., Proteins Struct. Funct. Genet., 20 (1994) 320.

    Google Scholar 

  15. 15.

    Jackson, R.M. and Sternberg, M.J.E., J. Mol. Biol., 250 (1995) 258.

    Google Scholar 

  16. 16.

    Fisher, D., Lin, S.L., Wolfson, H.J. and Nussinov, R., J. Mol. Biol., 248 (1995) 459.

    Google Scholar 

  17. 17.

    Norel, R., Lin, S.L., Wolfson, H.J. and Nussinov, R., J. Mol. Biol., 252 (1995) 263.

    Google Scholar 

  18. 18.

    Gabb, H.A., Jackson, R.M. and Sternberg, M.J., J. Mol. Biol., 272 (1997) 106.

    Google Scholar 

  19. 19.

    Jackson, R.M., Gabb, H.A. and Sternberg, M.J.E., J. Mol. Biol., 276 (1998) 265.

    Google Scholar 

  20. 20.

    Friedman, A.R., Roberts, V.A. and Tainer, J.A., Proteins Struct. Funct. Genet., 20 (1994) 15.

    Google Scholar 

  21. 21.

    Gehlhaar, D.K., Verkhivker, G.M., Rejto, P.A., Sherman, C.J., Fogel, D.B., Fogel, L.J. and Freer, S.T., Chem. Biol., 2 (1995) 317.

    Google Scholar 

  22. 22.

    Verkhivker, G.M., Rejto, P.A., Gehlhaar, D.K. and Freer, S.T., Proteins Struct. Funct. Genet., 25 (1996) 342.

    Google Scholar 

  23. 23.

    Rarey, M., Kramer, B., Lengauer, T. and Klebe, G., J. Mol. Biol., 261 (1996) 470.

    Google Scholar 

  24. 24.

    Rarey, M., Kramer, B. and Lengauer, T., J. Comput.-Aided Mol. Design, 11 (1997) 369.

    Google Scholar 

  25. 25.

    Welch, W., Ruppert, J. and Jain, A.N., Chem. Biol., 3 (1996) 449.

    Google Scholar 

  26. 26.

    Caflish, A., Niederer, P. and Anliker, M., Proteins Struct. Funct. Genet., 13 (1992) 223.

    Google Scholar 

  27. 27.

    Hart, T.N. and Read, R.J., Proteins Struct. Funct. Genet., 13 (1992) 206.

    Google Scholar 

  28. 28.

    Di Nola, A., Roccatano, D. and Berendsen, H.J.C., Proteins Struct. Funct. Genet., 19 (1994) 174.

    Google Scholar 

  29. 29.

    Clark, K.P. and Ajay, J. Comput. Chem., 16 (1995) 1210.

    Google Scholar 

  30. 30.

    Oshiro, C.M., Kuntz, I.D. and Dixon, J.S., J. Comput.-Aided Mol. Design, 9 (1995) 113.

    Google Scholar 

  31. 31.

    Jones, G., Willett, P., Glen, R.C., Leach, A.R. and Taylor R., J. Mol. Biol., 267 (1997) 727.

    Google Scholar 

  32. 32.

    Westhead, D.R., Clark, D.E. and Murray, C.W., J. Comput.-Aided Mol. Design, 11 (1997) 209.

    Google Scholar 

  33. 33.

    Baxter, C.A., Murray, C.W., Clark, D.E., Westhead, D.R. and Eldridge, M.D., Proteins Struct. Funct. Genet., 33 (1998) 367.

    Google Scholar 

  34. 34.

    Apostolakis, J., Pluckthun, A. and Caflish, A., J. Comput. Chem., 19 (1998) 21.

    Google Scholar 

  35. 35.

    Trosset, J.-Y. and Scheraga, H.A., J. Comput. Chem., 20 (1999) 244.

    Google Scholar 

  36. 36.

    Mangoni, M., Roccatano, D. and Di Nola, A., Proteins Struct. Funct. Genet., 35 (1999) 153.

    Google Scholar 

  37. 37.

    Leach, A.R., J. Mol. Biol., 235 (1994) 345.

    Google Scholar 

  38. 38.

    Desmet, J., Wilson, I.A., Joniau, M., De Mayer, M. and Lasters, I., Faseb J., 11 (1997) 164.

    Google Scholar 

  39. 39.

    Schaffer, L. and Verkhivker, G.M., Proteins Struct. Funct. Genet., 33 (1998) 295.

    Google Scholar 

  40. 40.

    Wasserman, Z.R. and Hodge, C.N., Proteins Struct. Funct. Genet., 24 (1996) 227.

    Google Scholar 

  41. 41.

    Totrov, M. and Abagyan, R., Nat. Struct. Biol., 1 (1994) 259.

    Google Scholar 

  42. 42.

    Totrov, M. and Abagyan, R., Proteins Struct. Funct. Genet., Supplement 1 (1997) 215.

    Google Scholar 

  43. 43.

    Sandak, B., Wolfson, H.J. and Nussinov, R., Proteins Struct. Funct. Genet., 32 (1998) 159.

    Google Scholar 

  44. 44.

    Lorber, D.M. and Shoichet, B.K., Protein Sci., 7 (1998) 938.

    Google Scholar 

  45. 45.

    Knegtel, R.M., Kuntz, I.D. and Oshiro, C.M., J. Mol. Biol., 266 (1997) 424.

    Google Scholar 

  46. 46.

    Bouzida, D., Rejto, P.A., Arthurs, S., Colson, A.B., Freer, S.T., Gehlhaar, D.K., Larson, V., Luty, B.A., Rose, P.W. and Verkhivker, G.M., Int. J. Quantum Chem., 72 (1999) 73.

    Google Scholar 

  47. 47.

    Carlson, H.A. and McCammon, J.A., Mol. Pharmacol., 57 (2000) 213.

    Google Scholar 

  48. 48.

    Bouzida, D., Arthurs, S., Colson, A.B., Freer, S.T., Gehlhaar, D.K., Larson, V., Luty, B.A., Rejto, P.A., Rose, P.W. and Verkhivker, G.M., In Altman, R.B., Dunker, A.K., Hunter, L., Klein, T. and Lauderdale, K. (Eds.), Pacific Symposium on Biocomputing-99, World Scientific, Singapore, 1999, pp. 426–437.

    Google Scholar 

  49. 49.

    Rejto, P.A. and Verkhivker, G.M., Proc. Natl. Acad. Sci. USA, 93 (1996) 8945.

    Google Scholar 

  50. 50.

    Oshiro, C.M. and Kuntz, I.D., Proteins Struct. Funct. Genet., 30 (1998) 321.

    Google Scholar 

  51. 51.

    Ewing, T.J.A. and Kuntz, I.D., J. Comput. Chem., 18 (1997) 1175.

    Google Scholar 

  52. 52.

    Sun, Y., Ewing, T.J.A., Skillman, A.G. and Kuntz, I.D., J. Comput.-Aided Mol. Design, 12 (1998) 597.

    Google Scholar 

  53. 53.

    Shortle, D., Simons, K.T. and Baker, D., Proc. Natl. Acad. Sci. USA, 95 (1998) 11158.

    Google Scholar 

  54. 54.

    Shah, N., Rejto, P.A. and Verkhivker, G.M., Proteins Struct. Funct. Genet., 28 (1997) 421.

    Google Scholar 

  55. 55.

    Rejto, P.A., Verkhivker, G.M., Gehlhaar, D.K. and Freer, S.T., in van Gunsteren, W., Weiner, P. and Wilkinson, A.J. (Eds.), Computational Simulation of Biomolecular Systems. ESCOM, Leiden, 1997, pp. 451–465.

    Google Scholar 

  56. 56.

    Bouzida, D., Rejto, P.A. and Verkhivker, G.M., Int. J. Quantum Chem., 73 (1999) 113.

    Google Scholar 

  57. 57.

    Rejto, P.A., Bouzida, D. and Verkhivker, G.M., Theor. Chem. Acc., 101 (1999) 138.

    Google Scholar 

  58. 58.

    Verkhivker, G.M., Rejto, P.A., Bouzida, D., Arthurs, S., Colson, A.B., Freer, S.T., Gehlhaar, D.K., Larson, V., Luty, B.A., Marrone, T. and Rose, P.W., J. Mol. Recognit., 12 (1999) 371.

    Google Scholar 

  59. 59.

    Mayo, S.L., Olafson, B.D. and Goddard, III, W.A., J. Phys. Chem., 94 (1990) 8897.

    Google Scholar 

  60. 60.

    Weiner, S.J., Kollman, P.A., Case, D.A., Singh, U.C., Chio, C., Alagona, G., Profeta, S. and Weiner, P., J. Am. Chem. Soc., 106 (1984) 765.

    Google Scholar 

  61. 61.

    Jorgensen, W. L. and Tirado-Rives, J., J. Am. Chem. Soc., 110 (1988) 1657.

    Google Scholar 

  62. 62.

    Stouten, P.F.W., Frömmel, C., Nakamura, H. and Sander, C., Mol. Simul., 10 (1993) 97.

    Google Scholar 

  63. 63.

    Dewar, M.J.S. and Thiel, W., J. Am. Chem. Soc., 99 (1977) 4899.

    Google Scholar 

  64. 64.

    Besler, B.H., Merz, Jr., K.M. and Kollman, P.A., J. Comput. Chem., 11 (1990) 431.

    Google Scholar 

  65. 65.

    Marinari, E. and Parisi, G., Europhys. Lett., 19 (1992) 451.

    Google Scholar 

  66. 66.

    Hukushima, K. and Nemoto, K., J. Phys. Soc., 65 (1996) 1604.

    Google Scholar 

  67. 67.

    Hansmann, U.H.E. and Okamoto, Y., Phys. Rev., E54 (1996) 5863.

    Google Scholar 

  68. 68.

    Hansmann, U.H.E. and Okamoto, Y., Phys. Rev., E56 (1997) 2228.

    Google Scholar 

  69. 69.

    Hansmann, U.H.E. and Okamoto, Y., J. Comput. Chem., 18 (1997) 920.

    Google Scholar 

  70. 70.

    Hansmann, U.H.E., Chem. Phys. Lett., 281 (1997) 140.

    Google Scholar 

  71. 71.

    Bouzida, D., Kumar, S. and Swendsen, R.H., Phys. Rev., A45 (1992) 8894.

    Google Scholar 

  72. 72.

    Ferrenberg, A.M. and Swendsen, R.H., Phys. Rev. Lett., 63 (1989) 1195.

    Google Scholar 

  73. 73.

    Boczko, E.M. and Brooks III, C.L., J. Phys. Chem., 97 (1993) 4509.

    Google Scholar 

  74. 74.

    Kumar, S., Bouzida, D., Swendsen, R.H., Kollman, P.A. and Rosenberg, J.M., J. Comput. Chem., 13 (1992) 1011.

    Google Scholar 

  75. 75.

    Kearsley, S.K., Acta Crystallogr., A45 (1989) 208.

    Google Scholar 

  76. 76.

    Morgan, H.L., J. Chem. Doc. 5 (1965) 107.

    Google Scholar 

  77. 77.

    Bawden, D., In Warr, W.A. (Ed.), Chemical Structures: The International Language of Chemistry, Springer-Verlag, Berlin, 1988, pp. 145–150.

    Google Scholar 

  78. 78.

    Shannon, C.E., The Bell System Techn. J., 27 (1948) 379.

    Google Scholar 

  79. 79.

    Hamilton, J.A., Steinrauf, L.K., Braden, B.C., Liepnieks, J., Benson, M.D., Holmgren, G., Sandgren, O. and Steen, L., J. Biol. Chem., 268 (1993) 2416.

    Google Scholar 

  80. 80.

    Steinrauf, L.K., Hamilton, J.A., Braden, B.C., Murrell, J.R. and Benson, M.D., J. Biol. Chem., 268 (1993) 2425.

    Google Scholar 

  81. 81.

    Lawson, C.L., van Montfort, R., Strokopytov, B., Rozeboom, H.J., Kalk, K.H., de Vries, G.E., Penninga, D., Dijkhuizen, L. and Dijkstra, B.W., J. Mol. Biol., 236 (1994) 590.

    Google Scholar 

  82. 82.

    Henrick, K., Collyer, C.A. and Blow, D., J. Mol. Biol., 208 (1989) 129.

    Google Scholar 

  83. 83.

    Dill, K.A., Protein Sci., 8 (1999) 1166.

    Google Scholar 

  84. 84.

    Bryngelson, J.D., Onuchic, J.N., Socci, N.D. and Wolynes, P.G., Proteins Struct. Funct. Genet., 21 (1995) 167.

    Google Scholar 

  85. 85.

    Dill, K.A., Bromberg, S., Yue, K., Fiebig, K.M., Yee, D.P., Thomas, P.D. and Chan, H.S., Protein Sci., 4 (1995) 561.

    Google Scholar 

  86. 86.

    Dill, K.A. and Chan, H.S., Nature Struct. Biol., 4 (1997) 10.

    Google Scholar 

  87. 87.

    Shakhnovich, E.I., Curr. Opin. Struct. Biol., 7 (1997) 29.

    Google Scholar 

  88. 88.

    Janin, J., Proteins Struct. Funct. Genet., 25 (1996) 438.

    Google Scholar 

  89. 89.

    Verkhivker, G.M. and Rejto, P.A., Proc. Natl. Acad. Sci. USA, 93 (1996) 60.

    Google Scholar 

  90. 90.

    Verkhivker, G.M. and Rejto, P.A., Proteins Struct. Funct. Genet., 28 (1997) 313.

    Google Scholar 

  91. 91.

    Tsai, C.-J., Xu, D. and Nussinov, R., Curr. Biol., 3 (1998) R71.

    Google Scholar 

  92. 92.

    Tsai, C.-J., Kumar, S., Ma, B. and Nussinov, R., Protein Sci., 8 (1999) 1181.

    Google Scholar 

  93. 93.

    Zhang, C., Chen, J. and DeLisi, C., Proteins Struct. Funct. Genet., 34 (1999) 255.

    Google Scholar 

  94. 94.

    Wlodawer, A. and Erickson, J.W., Annu. Rev. Biochem., 62 (1993) 543.

    Google Scholar 

  95. 95.

    Livhan, O., Bayer, E.A., Wilcheck, M. and Sussman, J.L., Proc. Natl. Acad. Sci. USA, 90 (1993) 5076.

    Google Scholar 

  96. 96.

    Weber, P.C., Wendolski, J.J., Pantoliano. M.W. and Salemme, F.R., J. Am. Chem. Soc., 114 (1992) 3197.

    Google Scholar 

  97. 97.

    Zhao, D., Arrowsmith, C.H., Jia, X. and Jardetzky, O., J. Mol. Biol., 229 (1993) 735.

    Google Scholar 

  98. 98.

    Rejto, P.A. and Freer, S.T., Prog. Biophys. Mol. Biol., 66 (1996) 167.

    Google Scholar 

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Verkhivker, G.M., Bouzida, D., Gehlhaar, D.K. et al. Deciphering common failures in molecular docking of ligand-protein complexes. J Comput Aided Mol Des 14, 731–751 (2000). https://doi.org/10.1023/A:1008158231558

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  • binding free energy profile
  • clustering
  • ligand-protein docking
  • molecular recognition
  • Monte Carlo simulations
  • structural similarity