Explicit Treatment of Water Molecules in Data-Driven Protein–Protein Docking: The Solvated HADDOCKing Approach

  • Panagiotis L. Kastritis
  • Aalt D. J. van Dijk
  • Alexandre M. J. J. Bonvin
Protocol
Part of the Methods in Molecular Biology book series (MIMB, volume 819)

Abstract

Water molecules are active components in, literally, every biochemical event, forming hydrogen bonds, filling cavities, and mediating interactions with other (bio)molecules. Therefore, solvent drastically affects the kinetics and thermodynamics of numerous cellular events, including protein–protein interactions. While docking techniques are becoming successful in predicting the three-dimensional structure of protein–protein complexes, they are still limited in accounting explicitly for water in the binding process. HADDOCK is one of the few programs so far that can explicitly deal with water molecules during docking. Its solvated docking protocol starts from hydrated molecules, and a fraction of the interfacial water is subsequently removed from the docked models in a biased Monte Carlo procedure. The Monte Carlo-based removal is based on interfacial amino acid—water contact propensities derived from a dataset of high-resolution crystal structures of protein–protein complexes. In this chapter, this solvated docking protocol is described and associated methodological aspects are illustrated through an application example. It is shown that, although docking results do not always improve when the solvated docking protocol is applied, scoring is improved and the positions of buried water molecules in an interface are correctly predicted. Therefore, by identifying important water molecules, solvated docking can aid the development of novel inhibitors of protein–protein complexes that might be better accommodated at an interface.

Key words

Protein complexes HADDOCK Protein–protein docking Explicit model Solvation shell Monte carlo Structure prediction Solvated docking 

Notes

Acknowledgments

This work was supported by the Netherlands Organization for Scientific Research (VICI Grant 700.56.442 to AMJJB and VENI Grant 863.08.027 to ADJvD) and the European Community (FP7 e-Infrastructure I3 projects eNMR (grant 213010) and WeNMR (grant 261572).

References

  1. 1.
    Levy, Y., and Onuchic, J. N. (2006) Water mediation in protein folding and molecular recognition, Annu Rev Biophys Biomol Struct 35, 389–415.PubMedCrossRefGoogle Scholar
  2. 2.
    Savage, H., and Wlodawer, A. (1986) Determination of water structure around biomolecules using X-ray and neutron diffraction methods, Methods Enzymol 127, 162–183.PubMedCrossRefGoogle Scholar
  3. 3.
    Halle, B. (2004) Biomolecular cryocrystallography: structural changes during flash-cooling, Proc Natl Acad Sci U S A 101, 4793–4798.PubMedCrossRefGoogle Scholar
  4. 4.
    Pal, S. K., and Zewail, A. H. (2004) Dynamics of water in biological recognition, Chem Rev 104, 2099–2123.PubMedCrossRefGoogle Scholar
  5. 5.
    Otting, G., Liepinsh, E., and Wuthrich, K. (1991) Protein hydration in aqueous solution, Science 254, 974–980.PubMedCrossRefGoogle Scholar
  6. 6.
    Park, S., and Saven, J. G. (2005) Statistical and molecular dynamics studies of buried waters in globular proteins, Proteins 60, 450–463.PubMedCrossRefGoogle Scholar
  7. 7.
    Petrone, P. M., and Garcia, A. E. (2004) MHC-peptide binding is assisted by bound water molecules, J Mol Biol 338, 419–435.PubMedCrossRefGoogle Scholar
  8. 8.
    Rodier, F., Bahadur, R. P., Chakrabarti, P., and Janin, J. (2005) Hydration of protein-protein interfaces, Proteins 60, 36–45.PubMedCrossRefGoogle Scholar
  9. 9.
    Cascales, E., Buchanan, S. K., Duche, D., Kleanthous, C., Lloubes, R., Postle, K., Riley, M., Slatin, S., and Cavard, D. (2007) Colicin biology, Microbiol Mol Biol Rev 71, 158–229.PubMedCrossRefGoogle Scholar
  10. 10.
    Meenan, N. A., Sharma, A., Fleishman, S. J., Macdonald, C. J., Morel, B., Boetzel, R., Moore, G. R., Baker, D., and Kleanthous, C. (2010) The structural and energetic basis for high selectivity in a high-affinity protein-protein interaction, Proc Natl Acad Sci U S A 107, 10080–10085.PubMedCrossRefGoogle Scholar
  11. 11.
    Buckle, A. M., Schreiber, G., and Fersht, A. R. (1994) Protein-protein recognition: crystal structural analysis of a barnase-barstar complex at 2.0-A resolution, Biochemistry 33, 8878–8889.PubMedCrossRefGoogle Scholar
  12. 12.
    Sevcik, J., Urbanikova, L., Dauter, Z., and Wilson, K. S. (1998) Recognition of RNase Sa by the inhibitor barstar: structure of the complex at 1.7 A resolution, Acta Crystallogr D Biol Crystallogr 54, 954–963.PubMedCrossRefGoogle Scholar
  13. 13.
    Bahadur, R. P., and Zacharias, M. (2008) The interface of protein-protein complexes: analysis of contacts and prediction of interactions, Cell Mol Life Sci 65, 1059–1072.PubMedCrossRefGoogle Scholar
  14. 14.
    Denisov, V. P., and Halle, B. (1995) Protein hydration dynamics in aqueous solution: a comparison of bovine pancreatic trypsin inhibitor and ubiquitin by oxygen-17 spin relaxation dispersion, J Mol Biol 245, 682–697.PubMedCrossRefGoogle Scholar
  15. 15.
    Lensink, M. F., Mendez, R., and Wodak, S. J. (2007) Docking and scoring protein complexes: CAPRI 3rd Edition, Proteins 69, 704–718.PubMedCrossRefGoogle Scholar
  16. 16.
    Lensink, M. F., and Wodak, S. J. (2010) Docking and scoring protein interactions: CAPRI 2009, Proteins 78, 3073–3084.PubMedCrossRefGoogle Scholar
  17. 17.
    Fernandez-Recio, J., Totrov, M., and Abagyan, R. (2004) Identification of protein-protein interaction sites from docking energy landscapes, J Mol Biol 335, 843–865.PubMedCrossRefGoogle Scholar
  18. 18.
    Fernandez-Recio, J., Abagyan, R., and Totrov, M. (2005) Improving CAPRI predictions: optimized desolvation for rigid-body docking, Proteins 60, 308–313.PubMedCrossRefGoogle Scholar
  19. 19.
    Zhou, R. (2003) Free energy landscape of protein folding in water: explicit vs. implicit solvent, Proteins 53, 148–161.PubMedCrossRefGoogle Scholar
  20. 20.
    Snow, C. D., Sorin, E. J., Rhee, Y. M., and Pande, V. S. (2005) How well can simulation predict protein folding kinetics and thermodynamics?, Annu Rev Biophys Biomol Struct 34, 43–69.PubMedCrossRefGoogle Scholar
  21. 21.
    de Vries, S. J., van Dijk, A. D., Krzeminski, M., van Dijk, M., Thureau, A., Hsu, V., Wassenaar, T., and Bonvin, A. M. (2007) HADDOCK versus HADDOCK: new features and performance of HADDOCK2.0 on the CAPRI targets, Proteins 69, 726–733.PubMedCrossRefGoogle Scholar
  22. 22.
    Dominguez, C., Boelens, R., and Bonvin, A. M. (2003) HADDOCK: a protein-protein docking approach based on biochemical or biophysical information, J Am Chem Soc 125, 1731–1737.PubMedCrossRefGoogle Scholar
  23. 23.
    de Vries, S. J., van Dijk, M., and Bonvin, A. M. (2010) The HADDOCK web server for data-driven biomolecular docking, Nat Protoc 5, 883–897.PubMedCrossRefGoogle Scholar
  24. 24.
    van Dijk, A. D., and Bonvin, A. M. (2006) Solvated docking: introducing water into the modelling of biomolecular complexes, Bioinformatics 22, 2340–2347.PubMedCrossRefGoogle Scholar
  25. 25.
    Keskin, O., Tsai, C. J., Wolfson, H., and Nussinov, R. (2004) A new, structurally nonredundant, diverse data set of protein-protein interfaces and its implications, Protein Sci 13, 1043–1055.PubMedCrossRefGoogle Scholar
  26. 26.
    Jorgensen, W. L., Chandrasekhar, J., Madura, J. D., Impey, R. W., and Klein, M. L. (1983) Comparison of simple potential functions for simulating liquid water, J Chem Phys 79, 926–935.CrossRefGoogle Scholar
  27. 27.
    Fuentes, G., van Dijk, A. D., and Bonvin, A. M. (2008) Nuclear magnetic resonance-based modeling and refinement of protein three-dimensional structures and their complexes, Methods Mol Biol 443, 229–255.PubMedCrossRefGoogle Scholar
  28. 28.
    van Dijk, A. D., Boelens, R., and Bonvin, A. M. (2005) Data-driven docking for the study of biomolecular complexes, FEBS J 272, 293–312.PubMedCrossRefGoogle Scholar
  29. 29.
    de Vries, S. J., and Bonvin, A. M. (2008) How proteins get in touch: interface prediction in the study of biomolecular complexes, Curr Protein Pept Sci 9, 394–406.PubMedCrossRefGoogle Scholar
  30. 30.
    Melquiond, A. S. J., and Bonvin, A. M. J. J. (2010) Data-driven docking: Using external information to spark the biomolecular rendez-vous, in Protein-protein complexes: Analysis, modeling and drug design (Zacharias, M., Ed.), pp 182–208, Imperial College Press, London.CrossRefGoogle Scholar
  31. 31.
    Martin, C., Richard, V., Salem, M., Hartley, R., and Mauguen, Y. (1999) Refinement and structural analysis of barnase at 1.5 A resolution, Acta Crystallogr D Biol Crystallogr 55, 386–398.PubMedCrossRefGoogle Scholar
  32. 32.
    Ratnaparkhi, G. S., Ramachandran, S., Udgaonkar, J. B., and Varadarajan, R. (1998) Discrepancies between the NMR and X-ray structures of uncomplexed barstar: analysis suggests that packing densities of protein structures determined by NMR are unreliable, Biochemistry 37, 6958–6966.PubMedCrossRefGoogle Scholar
  33. 33.
    de Vries, S. J., Melquiond, A. S., Kastritis, P. L., Karaca, E., Bordogna, A., van Dijk, M., Rodrigues, J. P., and Bonvin, A. M. (2010) Strengths and weaknesses of data-driven docking in critical assessment of prediction of interactions, Proteins 78 32423249.PubMedCrossRefGoogle Scholar
  34. 34.
    Karaca, E., Melquiond, A. S., de Vries, S. J., Kastritis, P. L., and Bonvin, A. M. (2010) Building macromolecular assemblies by information-driven docking: introducing the HADDOCK multibody docking server, Mol Cell Proteomics 9, 1784–1794.PubMedCrossRefGoogle Scholar
  35. 35.
    Kastritis, P. L., and Bonvin, A. M. (2010) Are scoring functions in protein-protein docking ready to predict interactomes? Clues from a novel binding affinity benchmark, J Proteome Res 9, 2216–2225.Google Scholar

Copyright information

© Springer Science+Business Media, LLC 2012

Authors and Affiliations

  • Panagiotis L. Kastritis
    • 1
  • Aalt D. J. van Dijk
    • 2
  • Alexandre M. J. J. Bonvin
    • 1
  1. 1.Bijvoet Center for Biomolecular ResearchUtrecht UniversityUtrechtThe Netherlands
  2. 2.Wageningen UR, Plant Research InternationalWageningenThe Netherlands

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