Journal of Computer-Aided Molecular Design

, Volume 7, Issue 5, pp 503–514 | Cite as

A new approach to analysis and display of local lipophilicity/hydrophilicity mapped on molecular surfaces

  • Wolfgang Heiden
  • Gerd Moeckel
  • J. Brickmann
Research Papers


A new method for display and analysis of lipophilic/hydrophilic properties on molecular surfaces is presented. The present approach is based on the concept of Crippen and coworkers that the overall hydrophobicity of a molecule (measured as the logarithm of the partition coefficient in an octanol/water system) can be obtained as a superposition of single atom contributions. It is also based on the concept of molecular lipophilicity potentials (MLP) first introduced by Audry and coworkers in order to establish a 3D lipophilicity potential profile in the molecular environment. Instead of using a l/r- or an exponential distance law between the atomic coordinates and a point on the molecular surface, a new distance dependency is introduced for the calculation of an MLP-value on the solvent-accessible surface of the molecule. In the present formalism the Crippen values (introduced for atoms in their characteristic structural environment) are ‘projected’ onto the van der Waals surface of the molecule by a special weighting procedure. This guarantees that only those atomic fragments contribute significantly to the surface values that are in the close neighbourhood of the surface point. This procedure not only works for small molecules but also allows the characterization of the surfaces of biological macromolecules by means of local lipophilicity. Lipophilic and hydrophilic domains can be recognized by visual inspection of computer-generated images or by computational procedures using fuzzy logic strategies. Local hydrophobicities on different molecular surfaces can be quantitatively compared on the basis of the present approach.

Key words

Hydrophobicity Lipophilicity Lipophilicity potential Hydrophobic interaction Partition coefficients 


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  1. 1.
    M.Delaage, Physico-chemical aspects of molecular recognition, In Delaage, M. (Ed.), Molecular Recognition Mechanisms, VCH Publishers, New York, 1991, pp. 1–14.Google Scholar
  2. 2.
    Kauzmann, W., Adv. Prot. Chem., 14 (1959) 1.Google Scholar
  3. 3.
    Suzuki, T. and Kudo, Y., J. Comput.-Aided Mol. Design, 4 (1990) 155.Google Scholar
  4. 4.
    Tanford, C., The Hydrophobic Effect: Formation of Micelles and Biological Membranes, Wiley, New York, 1973.Google Scholar
  5. 5.
    Fujita, T., Iwasa, J. and Hansch, C., J. Am. Chem. Soc., 86 (1964) 5175.Google Scholar
  6. 6.
    Nys, G.C. and Rekker, R.F., Chim. Thér., 8 (1973) 521.Google Scholar
  7. 7.
    Rekker, R.F., The Hydrophobic Fragmental Constants, Elsevier, New York, 1977.Google Scholar
  8. 8.
    Hansch, C. and Leo, A., Substituent Constants for Correlation Analysis in Chemistry and Biology, Wiley, New York, 1979.Google Scholar
  9. 9.
    Connemann, M., Untersuchungen zur Thermodynamik wässriger zweiphasiger Polymersysteme und Bestimmung-von Proteinverteilungskoeffizienten in diesen Extraktionssystemen, Thesis, Darmstadt, 1992.Google Scholar
  10. 10.
    Kellogg, G.E. and Abraham, D.J., J. Mol. Graphics, 10 (1992) 212.Google Scholar
  11. 11.
    Broto, P., Moreau, G. and Vandycke, C., Eur. J. Med. Chem. Chim. Thér., 19 (1984) 71.Google Scholar
  12. 12.
    Ghose, A.K. and Crippen, G.M., J. Comput. Chem., 7 (1986) 565.Google Scholar
  13. 13.
    Ghose, A.K., Pritchett, A. and Crippen, G.M., J. Comput. Chem. 9 (1988) 80.Google Scholar
  14. 14.
    Viswanadhan, V.N., Ghose, A.K., Revankar, G.R. and Robins, R.K., J. Chem. Inf. Comput. Sci., 29 (1989) 163.Google Scholar
  15. 15.
    Lichtenthaler, F.W., Immel, S. and Kreis, U., Starch/Stärke, 43 (1991) 121.Google Scholar
  16. 16.
    Lee, B. and Richards, F.M., J. Mol. Biol., 55 (1971) 379.Google Scholar
  17. 17.
    Connolly, M., Science, 221 (1983) 709.Google Scholar
  18. 18.
    Quarendon, P., Naylor, C.B. and Richards, W.G., J. Mol. Graphics, 2 (1984) 4.Google Scholar
  19. 19.
    Heiden, W., Schlenkrich, M. and Brickmann, J., J. Comput.-Aided Mol. Design, 4 (1990) 255.Google Scholar
  20. 20.
    Audry, E., Dubost, J.-P., Colleter, J.-C. and Dallet, P., Eur. J. Med. Chem. Chim. Thér., 21 (1986) 71.Google Scholar
  21. 21.
    Furet, P., Sele, A. and Cohen, N.C., J. Mol. Graphics, 6 (1988) 182.Google Scholar
  22. 22.
    Croizet, F., Langlois, M.H., Dubost, J.P., Braquet, P., Audry, E., Dallet, P. and Colleter, J.C., J. Mol. Graphics, 8 (1990) 153.Google Scholar
  23. 23.
    Eisenberg, D., Weiss, R.M. and Terwilliger, T.C., Nature, 299 (1982) 371.Google Scholar
  24. 24.
    Eisenberg, D. and McLachlan, A.D., Nature, 319 (1986) 199.Google Scholar
  25. 25.
    Fauchère, J.-L., Quarendon, P. and Kaetterer, L., J. Mol. Graphics, 6 (1988) 203.Google Scholar
  26. 26.
    Brasseur, R., J. Biol. Chem., 266 (1991) 16120.Google Scholar
  27. 27.
    Reif, F., Statistische Physik und Theorie der Wärme, 2nd edn., de Gruyter, Berlin, 1985, p. 454.Google Scholar
  28. 28.
    Heiden, W. and Brickmann, J., in preparation.Google Scholar
  29. 29.
    Moeckel, G., Heiden, W. and Brickmann, J., in preparation.Google Scholar

Copyright information

© ESCOM Science Publishers B.V 1993

Authors and Affiliations

  • Wolfgang Heiden
    • 1
  • Gerd Moeckel
    • 1
  • J. Brickmann
    • 1
  1. 1.Institut für Physikalische ChemieTechnische Hochschule DarmstadtDarmstadtGermany

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