Skip to main content
PMC home page
Protein Science : A Publication of the Protein Society logoLink to Protein Science : A Publication of the Protein Society
. 1996 Apr;5(4):614–626. doi: 10.1002/pro.5560050406

Prediction of protein complexes using empirical free energy functions.

Z Weng 1, S Vajda 1, C Delisi 1
PMCID: PMC2143396  PMID: 8845751

Abstract

A long sought goal in the physical chemistry of macromolecular structure, and one directly relevant to understanding the molecular basis of biological recognition, is predicting the geometry of bimolecular complexes from the geometries of their free monomers. Even when the monomers remain relatively unchanged by complex formation, prediction has been difficult because the free energies of alternative conformations of the complex have been difficult to evaluate quickly and accurately. This has forced the use of incomplete target functions, which typically do no better than to provide tens of possible complexes with no way of choosing between them. Here we present a general framework for empirical free energy evaluation and report calculations, based on a relatively complete and easily executable free energy function, that indicate that the structures of complexes can be predicted accurately from the structures of monomers, including close sequence homologues. The calculations also suggest that the binding free energies themselves may be predicted with reasonable accuracy. The method is compared to an alternative formulation that has also been applied recently to the same data set. Both approaches promise to open new opportunities in macromolecular design and specificity modification.

Full Text

The Full Text of this article is available as a PDF (3.6 MB).

Selected References

These references are in PubMed. This may not be the complete list of references from this article.

  1. Abagyan R., Totrov M. Biased probability Monte Carlo conformational searches and electrostatic calculations for peptides and proteins. J Mol Biol. 1994 Jan 21;235(3):983–1002. doi: 10.1006/jmbi.1994.1052. [DOI] [PubMed] [Google Scholar]
  2. Bacon D. J., Moult J. Docking by least-squares fitting of molecular surface patterns. J Mol Biol. 1992 Jun 5;225(3):849–858. doi: 10.1016/0022-2836(92)90405-9. [DOI] [PubMed] [Google Scholar]
  3. Bigler T. L., Lu W., Park S. J., Tashiro M., Wieczorek M., Wynn R., Laskowski M., Jr Binding of amino acid side chains to preformed cavities: interaction of serine proteinases with turkey ovomucoid third domains with coded and noncoded P1 residues. Protein Sci. 1993 May;2(5):786–799. doi: 10.1002/pro.5560020509. [DOI] [PMC free article] [PubMed] [Google Scholar]
  4. Cherfils J., Duquerroy S., Janin J. Protein-protein recognition analyzed by docking simulation. Proteins. 1991;11(4):271–280. doi: 10.1002/prot.340110406. [DOI] [PubMed] [Google Scholar]
  5. Chothia C., Janin J. Principles of protein-protein recognition. Nature. 1975 Aug 28;256(5520):705–708. doi: 10.1038/256705a0. [DOI] [PubMed] [Google Scholar]
  6. Colonna-Cesari F., Sander C. Excluded volume approximation to protein-solvent interaction. The solvent contact model. Biophys J. 1990 May;57(5):1103–1107. doi: 10.1016/S0006-3495(90)82630-8. [DOI] [PMC free article] [PubMed] [Google Scholar]
  7. Cramer C. J., Truhlar D. G. AM1-SM2 and PM3-SM3 parameterized SCF solvation models for free energies in aqueous solution. J Comput Aided Mol Des. 1992 Dec;6(6):629–666. doi: 10.1007/BF00126219. [DOI] [PubMed] [Google Scholar]
  8. Eisenberg D., McLachlan A. D. Solvation energy in protein folding and binding. Nature. 1986 Jan 16;319(6050):199–203. doi: 10.1038/319199a0. [DOI] [PubMed] [Google Scholar]
  9. Erickson H. P. Co-operativity in protein-protein association. The structure and stability of the actin filament. J Mol Biol. 1989 Apr 5;206(3):465–474. doi: 10.1016/0022-2836(89)90494-4. [DOI] [PubMed] [Google Scholar]
  10. Finkelstein A. V., Janin J. The price of lost freedom: entropy of bimolecular complex formation. Protein Eng. 1989 Oct;3(1):1–3. doi: 10.1093/protein/3.1.1. [DOI] [PubMed] [Google Scholar]
  11. Helmer-Citterich M., Tramontano A. PUZZLE: a new method for automated protein docking based on surface shape complementarity. J Mol Biol. 1994 Jan 21;235(3):1021–1031. doi: 10.1006/jmbi.1994.1054. [DOI] [PubMed] [Google Scholar]
  12. Hendsch Z. S., Tidor B. Do salt bridges stabilize proteins? A continuum electrostatic analysis. Protein Sci. 1994 Feb;3(2):211–226. doi: 10.1002/pro.5560030206. [DOI] [PMC free article] [PubMed] [Google Scholar]
  13. Horton N., Lewis M. Calculation of the free energy of association for protein complexes. Protein Sci. 1992 Jan;1(1):169–181. doi: 10.1002/pro.5560010117. [DOI] [PMC free article] [PubMed] [Google Scholar]
  14. Hubbard S. J., Campbell S. F., Thornton J. M. Molecular recognition. Conformational analysis of limited proteolytic sites and serine proteinase protein inhibitors. J Mol Biol. 1991 Jul 20;220(2):507–530. doi: 10.1016/0022-2836(91)90027-4. [DOI] [PubMed] [Google Scholar]
  15. Jackson R. M., Sternberg M. J. A continuum model for protein-protein interactions: application to the docking problem. J Mol Biol. 1995 Jul 7;250(2):258–275. doi: 10.1006/jmbi.1995.0375. [DOI] [PubMed] [Google Scholar]
  16. Jiang F., Kim S. H. "Soft docking": matching of molecular surface cubes. J Mol Biol. 1991 May 5;219(1):79–102. doi: 10.1016/0022-2836(91)90859-5. [DOI] [PubMed] [Google Scholar]
  17. Krystek S., Stouch T., Novotny J. Affinity and specificity of serine endopeptidase-protein inhibitor interactions. Empirical free energy calculations based on X-ray crystallographic structures. J Mol Biol. 1993 Dec 5;234(3):661–679. doi: 10.1006/jmbi.1993.1619. [DOI] [PubMed] [Google Scholar]
  18. Nicholls A., Sharp K. A., Honig B. Protein folding and association: insights from the interfacial and thermodynamic properties of hydrocarbons. Proteins. 1991;11(4):281–296. doi: 10.1002/prot.340110407. [DOI] [PubMed] [Google Scholar]
  19. Novotny J., Bruccoleri R. E., Saul F. A. On the attribution of binding energy in antigen-antibody complexes McPC 603, D1.3, and HyHEL-5. Biochemistry. 1989 May 30;28(11):4735–4749. doi: 10.1021/bi00437a034. [DOI] [PubMed] [Google Scholar]
  20. Ooi T., Oobatake M., Némethy G., Scheraga H. A. Accessible surface areas as a measure of the thermodynamic parameters of hydration of peptides. Proc Natl Acad Sci U S A. 1987 May;84(10):3086–3090. doi: 10.1073/pnas.84.10.3086. [DOI] [PMC free article] [PubMed] [Google Scholar]
  21. Page M. I., Jencks W. P. Entropic contributions to rate accelerations in enzymic and intramolecular reactions and the chelate effect. Proc Natl Acad Sci U S A. 1971 Aug;68(8):1678–1683. doi: 10.1073/pnas.68.8.1678. [DOI] [PMC free article] [PubMed] [Google Scholar]
  22. Pickett S. D., Sternberg M. J. Empirical scale of side-chain conformational entropy in protein folding. J Mol Biol. 1993 Jun 5;231(3):825–839. doi: 10.1006/jmbi.1993.1329. [DOI] [PubMed] [Google Scholar]
  23. Smith K. C., Honig B. Evaluation of the conformational free energies of loops in proteins. Proteins. 1994 Feb;18(2):119–132. doi: 10.1002/prot.340180205. [DOI] [PubMed] [Google Scholar]
  24. Stoddard B. L., Koshland D. E., Jr Prediction of the structure of a receptor-protein complex using a binary docking method. Nature. 1992 Aug 27;358(6389):774–776. doi: 10.1038/358774a0. [DOI] [PubMed] [Google Scholar]
  25. Tidor B., Karplus M. The contribution of vibrational entropy to molecular association. The dimerization of insulin. J Mol Biol. 1994 May 6;238(3):405–414. doi: 10.1006/jmbi.1994.1300. [DOI] [PubMed] [Google Scholar]
  26. Vajda S., Weng Z., Rosenfeld R., DeLisi C. Effect of conformational flexibility and solvation on receptor-ligand binding free energies. Biochemistry. 1994 Nov 29;33(47):13977–13988. doi: 10.1021/bi00251a004. [DOI] [PubMed] [Google Scholar]
  27. Vincent J. P., Lazdunski M. Trypsin-pancreatic trypsin inhibitor association. Dynamics of the interaction and role of disulfide bridges. Biochemistry. 1972 Aug 1;11(16):2967–2977. doi: 10.1021/bi00766a007. [DOI] [PubMed] [Google Scholar]
  28. Walls P. H., Sternberg M. J. New algorithm to model protein-protein recognition based on surface complementarity. Applications to antibody-antigen docking. J Mol Biol. 1992 Nov 5;228(1):277–297. doi: 10.1016/0022-2836(92)90506-f. [DOI] [PubMed] [Google Scholar]
  29. Wesson L., Eisenberg D. Atomic solvation parameters applied to molecular dynamics of proteins in solution. Protein Sci. 1992 Feb;1(2):227–235. doi: 10.1002/pro.5560010204. [DOI] [PMC free article] [PubMed] [Google Scholar]
  30. Wilson C., Mace J. E., Agard D. A. Computational method for the design of enzymes with altered substrate specificity. J Mol Biol. 1991 Jul 20;220(2):495–506. doi: 10.1016/0022-2836(91)90026-3. [DOI] [PubMed] [Google Scholar]

Articles from Protein Science : A Publication of the Protein Society are provided here courtesy of The Protein Society

RESOURCES