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Hydrophobic regions on protein surfaces

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Perspectives in Drug Discovery and Design

Abstract

Changes in solvation of ligand and receptor molecules during docking contribute essentially to the total energy of the binding process. In aqueous solution, the exposure of large hydrophobic surface regions is energetically unfavourable. Therefore, such surface elements are preferential binding sites and shielded from bulk water in the docking interface. In this review, physical approximations based on properties of the hydration shell structures and leading to the surface model of solvation are systematically analysed. The idea of atomic solvation parameters is shown to be applicable only to hydrophobic parts of the molecular surface. Additionally, the traditional concept of the solvent-accessible surface overestimates the hydrophobicity of molecules with both polar and non-polar solvent-exposed atomic groups. Only those hydrophobic surface regions that are not covered by first hydration shell water molecules can interact with bulk water. Methods for computing hydrophobic surface regions both with explicit models of water shells and with an incremental radial expansion of solvent-accessible polar atoms are considered in detail. The latter technique is shown to provide an easy and quick view of the likely hydrophobic surface regions available for hydrophobic ligand binding. As a literature review revealed, the specific hydrophobic surface energy appears in the range 12–30 cal/(molÅ2), but the exact value applicable for conformational and docking studies is still a matter of debate.

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References

  1. Eisenhaber, F., Persson, B. and Argos, P., Crit. Rev. Biochem. Mol. Biol., 30 (1995) 1.

    Google Scholar 

  2. Strynadka, N.C.J., Eisenstein, M., Katchalski-Katzir, E., Shoichet, B.K., Kuntz, I.D., Abagyan, R., Totrov, M., Janin, J., Cherfils, J., Zimmermann, F., Olson, A., Duncan, B., Rao, M., Jackson, R., Sternberg, M. and James, M.N.G., Nat. Struct. Biol., 3 (1996) 233.

    Google Scholar 

  3. Rupley, J.A. and Careri, G., Adv. Protein Chem., 41 (1991) 37.

    Google Scholar 

  4. Eisenhaber, F. and Argos, P., Protein Eng., 9 (1996) 1121.

    Google Scholar 

  5. Wüthrich, K., Otting, G. and Liepinsh, E., Faraday Discuss., 93 (1992) 35.

    Google Scholar 

  6. Levitt, M. and Park, B.H., Structure, 1 (1993) 223.

    Google Scholar 

  7. Steinhoff, H.-J., Kramm, B., Hess, G., Owerdieck, C. and Redhardt, A., Biophys. J., 65 (1993) 1486.

    Google Scholar 

  8. Phillips Jr., G.N. and Pettitt, B.M., Protein Sci., 4 (1995) 149.

    Google Scholar 

  9. Otting, G. and Liepinsh, E., Acc. Chem. Res., 28 (1995) 171.

    Google Scholar 

  10. Peemoeller, H., Yeomans, F.G., Kydon, D.W. and Sharp, A.R., Biophys. J., 49 (1986) 943.

    Google Scholar 

  11. Eisenmenger, F., Eisenhaber, F., Tumanyan, V.G. and Esipova, N.G., Studia Biophys., 98 (1984) 155.

    Google Scholar 

  12. Bryant, S.H., Proteins, 26 (1996) 172.

    Google Scholar 

  13. Herrmann, R.B., J. Phys. Chem., 76 (1972) 2754.

    Google Scholar 

  14. Reynolds, J.A., Gilbert, D.B. and Tanford, C., Proc. Natl. Acad. Sci. USA, 71 (1974) 2925.

    Google Scholar 

  15. Amidon, G.L., Yalkowsky, S.H., Anik, S.T. and Valvani, S.C., J. Phys. Chem., 79 (1975) 2239.

    Google Scholar 

  16. Valvani, S.C., Yalkowsky, S.H. and Amidon, G.L., J. Phys. Chem., 80 (1976) 829.

    Google Scholar 

  17. Herrmann, R.B., Proc. Natl. Acad. Sci. USA, 74 (1977) 4144.

    Google Scholar 

  18. Hopfinger, A.J., Macromolecules, 4 (1971) 731.

    Google Scholar 

  19. Hodes, Z.I., Nemethy, G. and Scheraga, H.A., Biopolymers, 18 (1979) 1565.

    Google Scholar 

  20. Hodes, Z.I., Nemethy, G. and Scheraga, H.A., Biopolymers, 18 (1979) 1611.

    Google Scholar 

  21. Kang, Y.K., Gibson, K.D., Nemethy, G. and Scheraga, H.A., J. Phys. Chem., 92 (1988) 4742.

    Google Scholar 

  22. Colonna-Cesari, F. and Sander, C., Biophys. J., 57 (1990) 1103.

    Google Scholar 

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

    Google Scholar 

  24. Luty, B.A., Wasserman, Z.R., Stouton, P.F.W., Hodge, C.N., Zacharias, M. and McCammon, J.A., J. Comput. Chem., 16 (1995) 454.

    Google Scholar 

  25. Augspurger, J.D. and Scheraga, H.A., J. Comput. Chem., 17 (1996) 1549.

    Google Scholar 

  26. Richards, F.M., Annu. Rev. Biophys. Bioeng., 6 (1995) 151.

    Google Scholar 

  27. Pauling, L., The Nature of the Chemical Bond, Cornell University, Ithaca, NY, 1960.

    Google Scholar 

  28. Bondi, A., Physical Properties of Molecular Crystals, Liquids and Glasses,Wiley, New York, NY, 1968.

    Google Scholar 

  29. Chothia, C., Nature, 254 (1975) 304.

    Google Scholar 

  30. Li, A. and Nussinov, R., Proteins, 18 (1998) 111.

    Google Scholar 

  31. Nyburg, S.C., Faerman, C.H. and Prasad, L., Acta Crystallogr., B43 (1987) 106.

    Google Scholar 

  32. Ikuta, S., Ishikawa, M., Katada, M. and Sano, H., Acta Crystallogr., B46 (1991) 23.

    Google Scholar 

  33. Steiner, T. and Saenger, W., Acta Crystallogr., B47 (1991) 1022.

    Google Scholar 

  34. Stone, A.J. and Tong, C.-S., J. Comput. Chem., 15 (1994) 1377.

    Google Scholar 

  35. Frömmel, C., J. Theor. Biol., 111 (1984) 247.

    Google Scholar 

  36. Eisenberg, D. and McLachlan, A.D., Nature, 319 (1986) 199.

    Google Scholar 

  37. Murphy, L.R., Matubayasi, N., Payne, V.A. and Levy, R.M., Folding Design, 3 (1998) 105.

    Google Scholar 

  38. Eisenhaber, F., Lijnzaad, P., Argos, P., Sander, C. and Scharf, M., J. Comput. Chem., 16 (1995) 273.

    Google Scholar 

  39. Bliznyuk, A.A. and Gready, J.E., J. Comput. Chem., 17 (1996) 962.

    Google Scholar 

  40. Bliznyuk, A.A. and Gready, J.E., J. Comput. Chem., 17 (1996) 970.

    Google Scholar 

  41. Richmond, T.J., J. Mol. Biol., 178 (1984) 63.

    Google Scholar 

  42. Kundrot, C.E., Ponder, J.W. and Richards, F.M., J. Comput. Chem., 12 (1991) 402.

    Google Scholar 

  43. Perrot, G., Cheng, B., Gibson, K.D., Vila, J., Palmer, K.A., Nayeem, A., Maigret, B. and Scheraga, H.A., J. Comput. Chem., 13 (1992) 1.

    Google Scholar 

  44. Cossi, M., Mennucci, B. and Cammi, R., J. Comput. Chem., 17 (1996) 57.

    Google Scholar 

  45. Von Freyberg, B. and Braun, W., J. Comput. Chem., 14 (1993) 510.

    Google Scholar 

  46. Von Freyberg, B., Richmond, T.J. and Braun, W., J. Mol. Biol., 233 (1993) 275.

    Google Scholar 

  47. Mumenthaler, C. and Braun, W., J. Mol. Modelling, 1 (1995) 1.

    Google Scholar 

  48. Schiffer, C.A., Caldwell, J.W., Kollman, P.A. and Stroud, R.M., Mol. Simul., 10 (1993) 121.

    Google Scholar 

  49. Zhang, H., Wong, C.F., Thacher, T. and Rabitz, H., Proteins, 23 (1995) 218.

    Google Scholar 

  50. Juffer, A., Eisenhaber, F., Hubbard, S.J., Walther, D. and Argos, P., Protein Sci., 4 (1995) 2499.

    Google Scholar 

  51. Juffer, A.H., Eisenhaber, F., Hubbard, S.J., Walther, D. and Argos, P., Protein Sci., 5 (1996) 1748.

    Google Scholar 

  52. Cummings, M.D., Hart, T.N. and Read, R.J., Protein Sci., 4 (1995) 2087.

    Google Scholar 

  53. Karplus, P.A., Protein Sci., 6 (1997) 1307.

    Google Scholar 

  54. Vajda, S., Weng, Z. and DeLisi, C., Protein Eng., 8 (1995) 1081.

    Google Scholar 

  55. Audry, E., Dubost, J.P., Colleter, J.C. and Dallet, Ph., Eur. J. Med. Chem.-Chim. Ther., 21 (1986) 71.

    Google Scholar 

  56. Furet, P., Sele, A. and Cohen, N.C., J. Mol. Graph., 6 (1988) 182.

    Google Scholar 

  57. Fauchère, J.-L., Quarendon, P. and Kaetterer, L., J. Mol. Graph., 6 (1988) 203.

    Google Scholar 

  58. Croizet, F., Langlois, M.H., Dubost, J.P., Braquet, P., Audry, E., Dallet, Ph. and Colleter, J.C., J. Mol. Graph., 8 (1990) 153.

    Google Scholar 

  59. Brasseur, R., J. Biol. Chem., 266 (1991) 16120.

    Google Scholar 

  60. Heiden, W., Moeckel, G. and Brickmann, J., J. Comput.-Aided Mol. Design, 7 (1993) 503.

    Google Scholar 

  61. Young, L., Jernigan, R.L. and Covell, D.G., Protein Sci., 3 (1994) 717.

    Google Scholar 

  62. Du, Q. and Arteca, G.A., J. Comput.-Aided Mol. Design, 10 (1996) 133.

    Google Scholar 

  63. Du, Q., Arteca, G.A. and Mezey, P.G., J. Comput.-Aided Mol. Design, 11 (1997) 503.

    Google Scholar 

  64. Vedani, A. and Huhta, D., J. Am. Chem. Soc., 113 (1991) 5860.

    Google Scholar 

  65. Pitt, W.R., Murray-Rust, J. and Goodfellow, J.M., J. Comput. Chem., 14 (1993) 1007.

    Google Scholar 

  66. Zheng, Ch., Wong, Ch.F. and McCammon, J.A., Biopolymers, 29 (1990) 1877.

    Google Scholar 

  67. Eisenhaber, F., Mannik, J.H. and Tumanyan, V.G., Biopolymers, 29 (1990) 1453.

    Google Scholar 

  68. Eisenhaber, F., Tumanyan, V.G. and Abagyan, R.A., Biopolymers, 30 (1990) 563.

    Google Scholar 

  69. Eisenhaber, F. and Schulz, W., Biopolymers, 32 (1992) 1643.

    Google Scholar 

  70. Brunne, R.M., Liepinsh, E., Otting, G., Wüthrich, K. and van Gunsteren, W.F., J. Mol. Biol., 231 (1993) 1040.

    Google Scholar 

  71. Lounnas, V. and Pettitt, B.M., Proteins, 18 (1994) 133.

    Google Scholar 

  72. Lounnas, V. and Pettitt, B.M., Proteins, 18 (1994) 148.

    Google Scholar 

  73. Lounnas, V., Pettitt, B.M. and Phillips Jr., G.N., Biophys. J., 66 (1994) 601.

    Google Scholar 

  74. Rao, S.T., Wu, S., Satyshur, K.A., Ling, K.-Y., Kung, C. and Sundaralingam, M., Protein Sci., 2 (1993) 436.

    Google Scholar 

  75. Vogel, H.J., Biochem. Cell Biol., 72 (1994) 357.

    Google Scholar 

  76. Wintrode, P.L. and Privalov, P.L., J. Mol. Biol., 266 (1997) 1050.

    Google Scholar 

  77. Prange, T., Schiltz, M., Pernot, L., Colloc'h, N., Longhi, S., Bourguet, W. and Fourme, R., Proteins, 30 (1998) 61.

    Google Scholar 

  78. Rees, D.C. and Wolfe, G.M., Protein Sci., 2 (1993) 1882.

    Google Scholar 

  79. Eisenhaber, F., Protein Sci., 5 (1996) 1676.

    Google Scholar 

  80. Ooi, T., Oobatake, M., Nemethy, G. and Scheraga, H.A., Proc. Natl. Acad. Sci. USA, 84 (1987) 3086.

    Google Scholar 

  81. Eisenberg, D., Wesson, M. and Yamashita, M., Chem. Scripta, 29A (1989) 217.

    Google Scholar 

  82. Wesson, L. and Eisenberg, D., Protein Sci., 1 (1992) 227.

    Google Scholar 

  83. Koehl, P. and Delarue, M., Proteins, 20 (1994) 264.

    Google Scholar 

  84. Eriksson, A.E., Baase, W.A., Zhang, X.-J., Heinz, D.W., Blaber, M., Baldwin, E.P. and Matthews, B.W., Science, 255 (1992) 178.

    Google Scholar 

  85. Eriksson, A.E., Baase, W.A. and Matthews, B.W., J. Mol. Biol., 229 (1993) 747.

    Google Scholar 

  86. Pinker, R.J., Rose, G.D. and Kallenbach, N.R., Protein Sci., 2 (1993) 1099.

    Google Scholar 

  87. Vallone, B., Miele, A.E., Vecchini, P., Chiancone, E. and Brunori, M., Proc. Natl. Acad. Sci. USA, 95 (1998) 6103.

    Google Scholar 

  88. Wang, Y., Zhang, H. and Scott, R.A., Protein Sci., 4 (1995) 1402.

    Google Scholar 

  89. Lemieux, R.U., Acc. Chem. Res., 29 (1996) 373.

    Google Scholar 

  90. Argos, P., Protein Eng., 2 (1988) 101.

    Google Scholar 

  91. Janin, J., Miller, S. and Chothia, C., J. Mol. Biol., 204 (1988) 155.

    Google Scholar 

  92. Miller, S., Protein Eng., 3 (1989) 77.

    Google Scholar 

  93. Janin, J. and Chothia, C., J. Biol. Chem., 265 (1990) 1627.

    Google Scholar 

  94. Korn, A.P. and Burnett, R.M., Proteins, 9 (1991) 37.

    Google Scholar 

  95. Jones, S. and Thornton, J.M., Proc. Natl. Acad. Sci. USA, 93 (1996) 13.

    Google Scholar 

  96. Tsai, C.-J., Lin, S.L., Wolfson, H.J. and Nussinov, R., Crit. Rev. Biochem. Mol. Biol., 31 (1996) 127.

    Google Scholar 

  97. Jones, S. and Thornton, J.M., J. Mol. Biol., 272 (1997) 121.

    Google Scholar 

  98. Jones, S. and Thornton, J.M., J. Mol. Biol., 272 (1997) 133.

    Google Scholar 

  99. Tsai, C.-J., Lin, S.L., Wolfson, H.J. and Nussinov, R., Protein Sci., 6 (1997) 53.

    Google Scholar 

  100. Conte, L.L., Chothia, C. and Janin, J., J. Mol. Biol., 285 (1999) 2177.

    Google Scholar 

  101. Lijnzaad, P. and Argos, P., Proteins, 28 (1997) 333.

    Google Scholar 

  102. Tisi, L.C. and Evans, P.A., J. Mol. Biol., 249 (1995) 251.

    Google Scholar 

  103. Uversky, V.N. and Ptitsyn, O.B., J. Mol. Biol., 255 (1996) 215.

    Google Scholar 

  104. Causette, M., Planche, H., Delepine, S., Monsan, P., Gaunand, A. and Lindet, B., Protein Eng., 10 (1997) 1235.

    Google Scholar 

  105. Kuehner, D.E., Heyer, C., Rämsch, C., Fornefeld, U.M., Blanch, H.W. and Prausnitz, J.M., Biophys. J., 73 (1997) 3211.

    Google Scholar 

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  1. Institute of Molecular Pathology, Dr. Bohr-Gasse 7, A-1030, Vienna, Austria

    Frank Eisenhaber

  2. European Molecular Biology Laboratory, Meyerhofstrasse 1, D-69012, Heidelberg, Germany

    Frank Eisenhaber

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Eisenhaber, F. Hydrophobic regions on protein surfaces. Perspectives in Drug Discovery and Design 17, 27–42 (1999). https://doi.org/10.1023/A:1008766422140

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