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Very empirical treatment of solvation and entropy: a force field derived from Log Po/w

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Abstract

A non-covalent interaction force field model derived from the partition coefficient of 1-octanol/water solubility is described. This model, HINT for Hydropathic INTeractions, is shown to include, in very empirical and approximate terms, all components of biomolecular associations, including hydrogen bonding, Coulombic interactions, hydrophobic interactions, entropy and solvation/desolvation. Particular emphasis is placed on: (1) demonstrating the relationship between the total empirical HINT score and free energy of association, ΔG interaction; (2) showing that the HINT hydrophobic-polar interaction sub-score represents the energy cost of desolvation upon binding for interacting biomolecules; and (3) a new methodology for treating constrained water molecules as discrete independent small ligands. An example calculation is reported for dihydrofolate reductase (DHFR) bound with methotrexate (MTX). In that case the observed very tight binding, ΔG interaction≤−13.6 kcal mol−1, is largely due to ten hydrogen bonds between the ligand and enzyme with estimated strength ranging between −0.4 and −2.3 kcal mol−1. Four water molecules bridging between DHFR and MTX contribute an additional −1.7 kcal mol−1 stability to the complex. The HINT estimate of the cost of desolvation is +13.9 kcal mol−1.

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References

  1. Petukhov, M., Cregut, D., Soares, C.M. and Serrano, L., Protein Sci., 8 (1999) 1982.

    Google Scholar 

  2. Royer, W.E., Jr., Pardanani, A., Gibson, Q.H., Peterson, E.S. and Friedman, J.M., Proc. Natl. Acad. Sci. USA, 93 (1996) 14526.

    Google Scholar 

  3. Bhat, T.N., Bentley, G.A., Boulot, G., Greene, M.I., Tello, D., Dall'Acqua, W., Souchon, S., Schwarz, F.P., Mariuzza, R.A. and Poljak, R.J., Proc. Natl. Acad. Sci. USA, 91 (1994) 1089.

    Google Scholar 

  4. Berman, H.M, Westbrook, J., Feng, Z., Gilliland, G., Bhat, T.N., Weissig, H., Shindyalov, I.N. and Bourne, P.E., Nucl. Acids Res., 28 (2000) 235.

    Google Scholar 

  5. Dixon, R.W. and Kollman, P.A., Proteins Struct. Funct. Genet., 36 (1999) 471.

    Google Scholar 

  6. Cornell, W.D., Cieplak, P. and Bayly, CI., J. Am. Chem. Soc., 117 (1995) 5179.

    Google Scholar 

  7. Jones-Hertzog, D.K. and Jorgensen, W.L., J. Med. Chem., 40 (1997) 1539.

    Google Scholar 

  8. Aqvist, J., Medina, C. and Samuelsson, J.E., Protein Eng., 7 (1994) 385.

    Google Scholar 

  9. Reddy, M.R., Varney, M.D., Kalish, V., Viswanadhan, V.N. and Appelt, K., J. Med. Chem., 37 (1994) 1145.

    Google Scholar 

  10. Rao, B.G., Tilton, R.F. and Singh, U.C., J. Am. Chem. Soc., 114 (1992) 4447.

    Google Scholar 

  11. Massova, I. and Kollman, P.A., J. Am. Chem. Soc., 121 (1999) 8133.

    Google Scholar 

  12. Gao, J., Kuczera, K., Tidor, B. and Karplus, M., Science, 244 (1989) 1069.

    Google Scholar 

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

    Google Scholar 

  14. Zeng, J., Fridman, M., Maruta, H., Treutlein, H.R. and Simonson, T., Protein Sci., 8 (1999) 50.

    Google Scholar 

  15. Venkatarangan, P. and Hopfinger, A.J., J. Med. Chem., 42 (1999) 2169.

    Google Scholar 

  16. Pearlman, D.A. and Connelly, P.R., J. Mol. Biol., 248 (1995) 696.

    Google Scholar 

  17. Tawa, G.J., Topol, I.A., Burt, S.K. and Erickson, J.W., J. Am. Chem. Soc., 120 (1998) 8856.

    Google Scholar 

  18. Kellogg, G.E., Med. Chem. Res., 9 (1999) 439. 393

    Google Scholar 

  19. Tanford, C., The Hydrophobic Effect: Formation of Micelles and Biological Membranes, 2nd edition, Wiley, New York, NY, 1980.

    Google Scholar 

  20. Lum, K., Chandler, D. and Weeks, J.D., J. Phys. Chem. 103 (1999) 4570.

    Google Scholar 

  21. Tsai, C.J. and Nussinov, R., Prot. Sci., 6 (1997) 24.

    Google Scholar 

  22. Roseman, M.A., J. Mol. Biol., 200 (1988) 513.

    Google Scholar 

  23. Eisenberg, D., Wilcox, W. and McLachlan, A.D., J. Cell Biochem., 31 (1986) 11.

    Google Scholar 

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

    Google Scholar 

  25. White, S.H. and Jacobs, R.E., J. Membrane Biol., 115 (1990) 145.

    Google Scholar 

  26. Westkaemper, R.B. and Glennon, R.A., Med. Chem. Res., 3 (1993) 317.

    Google Scholar 

  27. Hansch, C., Leo, A., Exploring QSAR. Fundamentals and Applications in Chemistry and Biology, American Chemical Society, Washington, 1995.

    Google Scholar 

  28. Hansch, C., Steward, A.R., Anderson, S.M. and Bentley, D., J. Med. Chem., 11 (1968) 1.

    Google Scholar 

  29. Mannhold, R. and Rekker, R.F., Persp. Drug Discov. Design, 18 (2000) 1.

    Google Scholar 

  30. Mannhold, R. and Dross, K., Quant. Struct. Act. Relat., 15 (1996) 403.

    Google Scholar 

  31. Leo, A.J., Chem. Rev., 93 (1993) 1281.

    Google Scholar 

  32. Wireko, F.C., Kellogg, G.E. and Abraham, D.J., J. Med. Chem., 34 (1991) 758.

    Google Scholar 

  33. Kellogg, G.E., Semus, S.F. and Abraham, D.J., J. Comput. Aided Mol. Des., 5 (1991) 545.

    Google Scholar 

  34. Kellogg, G.E., Joshi, G.S. and Abraham, D.J., Med. Chem. Res., 1 (1992) 444.

    Google Scholar 

  35. Abraham, D.J., Kellogg, G.E., Holt, J.M. and Ackers, G.K., J. Mol. Biol., 272 (1997) 613.

    Google Scholar 

  36. Kellogg, G.E. and Abraham, D.J., Eur. J. Med. Chem., 35 (2000), 651.

    Google Scholar 

  37. Burnett, J.C., Kellogg, G.E. and Abraham, D.J., Biochem. 39 (2000) 1622.

    Google Scholar 

  38. Hansch, C. and Leo, A.J., Substituent Constants for Correlation Analysis in Chemistry and Biology, Wiley, New York, NY, 1979.

    Google Scholar 

  39. Kyte, J. and Doolittle, R.F., J. Mol. Biol., 57 (1982) 105.

    Google Scholar 

  40. Isrealachvili, J. and Pashley, R., Nature, 300 (1982) 341.

    Google Scholar 

  41. Abraham, D.J. and Leo, A.J., Proteins, 2 (1987) 130.

    Google Scholar 

  42. Abraham, D.J. and Kellogg, G.E., J. Comput. Aided Mol. Des., 8 (1994) 41.

    Google Scholar 

  43. Dill, K.A., J. Biol. Chem., 272 (1997) 701.

    Google Scholar 

  44. Nemethy, G. and Scheraga, H., J. Chem. Phys., 36 (1962) 3382.

    Google Scholar 

  45. Nemethy, G. and Scheraga, H., J. Phys. Chem., 66 (1962) 1773.

    Google Scholar 

  46. Ben-Naim A., Hydrophobic Interactions, Plenum, New York, NY, 1980.

    Google Scholar 

  47. Tsai, R.S., Fan, W.Z., ElTayar, N., Carrupt, P.A., Testa, B. and Kier, L., J. Am. Chem. Soc., 115 (1993) 9632.

    Google Scholar 

  48. Fan, W.Z., Tsai, R.S., ElTayar, N., Carrupt, P.A. and Testa, B., J. Phys. Chem., 98 (1994) 329.

    Google Scholar 

  49. Fermi, G., Perutz, M.F., Shaanan, B. and Fourme R., J. Mol. Biol., 175 (1984) 159.

    Google Scholar 

  50. Shaanan, B., J. Mol. Biol., 171 (1983) 31.

    Google Scholar 

  51. Smith, F.R., Lattman, E.E. and Carter, C.W., Jr., Proteins: Struct. Funct. Genet., 10 (1991) 81.

    Google Scholar 

  52. Kavanaugh, J.S., Weydert, J.S. and Ackers, G. K., Biochemistry, 37 (1998) 4358.

    Google Scholar 

  53. Kavanaugh, J.S., Rogers, P.H., Case, D.A. and Arnone, A., Biochemistry, 31 (1992) 4111.

    Google Scholar 

  54. Harrington, D.J., Adachi, K. and Royer, W.E., Jr., J. Biol. Chem., 273 (1998) 32690.

    Google Scholar 

  55. Ishimori, K., Morishima, I., Imai, K., Fushitani, K., Miyazaki, G., Shih, D., Tame, J., Pegnier, J. and Nigai, K., J. Biol. Chem., 264 (1989) 14624.

    Google Scholar 

  56. Kavanaugh, J.S., Chafin, D.R., Arnone, A., Mozzarelli, A., Rivetti, C., Rossi, G.L., Kwiatkowski, L.D. and Noble, R.W., J. Mol. Biol., 248 (1995) 136.

    Google Scholar 

  57. Silva, M.M., Rogers, P.H. and Arnone, A., J. Biol. Chem., 267 (1992) 17248.

    Google Scholar 

  58. Turner, G.J., Galacteros, F., Doyle, M.L., Hedlund, B., Pettigrew, D.W., Turner, B.W., Smithm F.R., Moo-Pen, W., Rucknagel, D.L. and Ackers, G.K., Proteins: Struct. Funct. Genet., 14 (1992) 333.

    Google Scholar 

  59. LiCata, V.J., Dalessio, P.M. and Ackers, G.K., Proteins: Struct. Funct. Genet., 17 (1993) 279.

    Google Scholar 

  60. Kiger, L., Klinger, A.L., Kwiatkowski, L.D., Young, A.D., Doyle, M.L., Holt, J.M., Noble, R.W. and Ackers, G.K., Biochemistry, 37 (1988) 4336.

    Google Scholar 

  61. Burnett, J.C., Botti, P., Abraham, D.J. and Kellogg, G.E., Proteins Struct. Funct. Genet. Proteins: Struct. Fund. Genet., 42 (2001) 355-377.

    Google Scholar 

  62. Goodford, P.J., J. Med. Chem., 28 (1985) 857.

    Google Scholar 

  63. Gilson, M.K. and Honig, B., Proteins: Struct. Funct. Genet., 4 (1988) 7.

    Google Scholar 

  64. Burchall, J.J., in Hitchings, G.H. (Ed.), Inhibition of Folate Metabolism in Chemotherapy. The Origins and Uses of Cotrimoxazole, Springer-Verlag, Berlin, 1983, pp. 55-74.

    Google Scholar 

  65. Burchall, J.J., in Sirotnak, F.M., Burchall, J.J., Ensminger, W.B. and Montgomery, J.A. (Eds), Folate Antagonists as Therapeutic Agents 1. Biochemistry, MolecularActions, and Synthetic Design, Academic, Orlando, 1984, pp. 133-150.

    Google Scholar 

  66. Montgomery, J.A. and Piper, J.R., in reference 32b, pp. 219-260.

  67. Sawaya, M.R. and Kraut, J. Biochemistry, 36 (1997) 586.

    Google Scholar 

  68. Molecular Simulations, Inc., San Diego CA.

  69. Levitt, M. and Perutz, M.F., J. Mol. Biol., 201 (1988) 751.

    Google Scholar 

  70. Perutz, M.F., Fermi, G., Abraham, D.J., Poyart, C. and Bursaux, E., J. Am. Chem. Soc., 108 (1986) 1064.

    Google Scholar 

  71. Burley, S.K. and Petsko, FEBS Lett., 203 (1986) 139.

    Google Scholar 

  72. Holdgate, G.A., Tunnicliffe, A., Ward, W.H.J., Weston, S.A., Rosenbrock, G., Barth, P.T., Taylor, I.W.F., Pauptit, R.A. and Timms, D., Biochem., 36 (1997) 9663.

    Google Scholar 

  73. Hisler, V.J., Gomez, J. and Freire, E., Proteins Struct. Funct. Genet., 26 (1996) 123.

    Google Scholar 

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  1. Institute for Structural Biology and Drug Discovery & Department of Medicinal Chemistry, School of Pharmacy, Virginia Commonwealth University, Richmond, VA, 23298-0133, USA

    Glen Eugene Kellogg, James C. Burnett & Donald J. Abraham

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  1. Glen Eugene Kellogg
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Kellogg, G.E., Burnett, J.C. & Abraham, D.J. Very empirical treatment of solvation and entropy: a force field derived from Log Po/w. J Comput Aided Mol Des 15, 381–393 (2001). https://doi.org/10.1023/A:1011136228678

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