Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Protocol
  • Published:

Predicting protein-protein interactions on a proteome scale by matching evolutionary and structural similarities at interfaces using PRISM

Nature Protocols volume 6, pages 1341–1354 (2011)Cite this article

Subjects

Abstract

Prediction of protein-protein interactions at the structural level on the proteome scale is important because it allows prediction of protein function, helps drug discovery and takes steps toward genome-wide structural systems biology. We provide a protocol (termed PRISM, protein interactions by structural matching) for large-scale prediction of protein-protein interactions and assembly of protein complex structures. The method consists of two components: rigid-body structural comparisons of target proteins to known template protein-protein interfaces and flexible refinement using a docking energy function. The PRISM rationale follows our observation that globally different protein structures can interact via similar architectural motifs. PRISM predicts binding residues by using structural similarity and evolutionary conservation of putative binding residue 'hot spots'. Ultimately, PRISM could help to construct cellular pathways and functional, proteome-scale annotation. PRISM is implemented in Python and runs in a UNIX environment. The program accepts Protein Data Bank–formatted protein structures and is available at http://prism.ccbb.ku.edu.tr/prism_protocol/.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Figure 1: Description of the prediction algorithm.
Figure 2
Figure 3: The putative Chk1-p16ink complex predicted by PRISM using templates 1blxAB and 1fmaDE.

Similar content being viewed by others

References

  1. Kleanthous, C. Protein-Protein Recognition: Frontiers in Molecular Biology (Oxford University Press, 2001).

  2. Gavin, A.C. et al. Functional organization of the yeast proteome by systematic analysis of protein complexes. Nature 415, 141–147 (2002).

    Article  CAS  PubMed  Google Scholar 

  3. Uetz, P. et al. A comprehensive analysis of protein-protein interactions in Saccharomyces cerevisiae. Nature 403, 623–627 (2000).

    Article  CAS  PubMed  Google Scholar 

  4. Bader, G.D., Betel, D. & Hogue, C.W. BIND: the Biomolecular Interaction Network Database. Nucleic Acids Res. 31, 248–250 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Xenarios, I. et al. DIP, the Database of Interacting Proteins: a research tool for studying cellular networks of protein interactions. Nucleic Acids Res. 30, 303–305 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Berman, H.M. et al. The protein data bank. Nucleic Acids Res. 28, 235–242 (2000).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Bogan, A.A. & Thorn, K.S. Anatomy of hot spots in protein interfaces. J. Mol. Biol. 280, 1–9 (1998).

    Article  CAS  PubMed  Google Scholar 

  8. Pazos, F., Helmer-Citterich, M., Ausiello, G. & Valencia, A. Correlated mutations contain information about protein-protein interaction. J. Mol. Biol. 271, 511–523 (1997).

    Article  CAS  PubMed  Google Scholar 

  9. Andrusier, N., Mashiach, E., Nussinov, R. & Wolfson, H.J. Principles of flexible protein-protein docking. Proteins 73, 271–289 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Gray, J.J. High-resolution protein-protein docking. Curr. Opin. Struct. Biol. 16, 183–193 (2006).

    Article  CAS  PubMed  Google Scholar 

  11. Halperin, I., Ma, B., Wolfson, H. & Nussinov, R. Principles of docking: an overview of search algorithms and a guide to scoring functions. Proteins 47, 409–443 (2002).

    Article  CAS  PubMed  Google Scholar 

  12. de Vries, S.J., van Dijk, M. & Bonvin, A.M. The HADDOCK web server for data-driven biomolecular docking. Nat. Protoc. 5, 883–897 (2010).

    Article  CAS  PubMed  Google Scholar 

  13. Lesk, V.I. & Sternberg, M.J. 3D-Garden: a system for modelling protein-protein complexes based on conformational refinement of ensembles generated with the marching cubes algorithm. Bioinformatics 24, 1137–1144 (2008).

    Article  CAS  PubMed  Google Scholar 

  14. Cheng, T.M., Blundell, T.L. & Fernandez-Recio, J. pyDock: electrostatics and desolvation for effective scoring of rigid-body protein-protein docking. Proteins 68, 503–515 (2007).

    Article  CAS  PubMed  Google Scholar 

  15. Chen, R., Li, L. & Weng, Z. ZDOCK: an initial-stage protein-docking algorithm. Proteins 52, 80–87 (2003).

    Article  CAS  PubMed  Google Scholar 

  16. Schneidman-Duhovny, D., Inbar, Y., Nussinov, R. & Wolfson, H.J. PatchDock and SymmDock: servers for rigid and symmetric docking. Nucleic Acids Res. 33, W363–W367 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Caffrey, D.R., Somaroo, S., Hughes, J.D., Mintseris, J. & Huang, E.S. Are protein-protein interfaces more conserved in sequence than the rest of the protein surface? Protein Sci. 13, 190–202 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Keskin, O., Tsai, C.J., Wolfson, H. & Nussinov, R. A new, structurally nonredundant, diverse data set of protein-protein interfaces and its implications. Protein Sci. 13, 1043–1055 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Tsai, C.J., Lin, S.L., Wolfson, H.J. & Nussinov, R. A dataset of protein-protein interfaces generated with a sequence-order-independent comparison technique. J. Mol. Biol. 260, 604–620 (1996).

    Article  CAS  PubMed  Google Scholar 

  20. Tsai, C.J., Lin, S.L., Wolfson, H.J. & Nussinov, R. Protein-protein interfaces: architectures and interactions in protein-protein interfaces and in protein cores. Their similarities and differences. Crit. Rev. Biochem. Mol. Biol. 31, 127–152 (1996).

    Article  CAS  PubMed  Google Scholar 

  21. Keskin, O. & Nussinov, R. Similar binding sites and different partners: implications to shared proteins in cellular pathways. Structure 15, 341–354 (2007).

    Article  CAS  PubMed  Google Scholar 

  22. Aytuna, A.S., Gursoy, A. & Keskin, O. Prediction of protein-protein interactions by combining structure and sequence conservation in protein interfaces. Bioinformatics 21, 2850–2855 (2005).

    Article  CAS  PubMed  Google Scholar 

  23. Ogmen, U., Keskin, O., Aytuna, A.S., Nussinov, R. & Gursoy, A. PRISM: protein interactions by structural matching. Nucleic Acids Res. 33, W331–W336 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Keskin, O., Nussinov, R. & Gursoy, A. PRISM: protein-protein interaction prediction by structural matching. Methods Mol. Biol. 484, 505–521 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Kar, G., Gursoy, A. & Keskin, O. Human cancer protein-protein interaction network: a structural perspective. PLoS Comput. Biol. 5, e1000601 (2009).

    Article  PubMed  PubMed Central  Google Scholar 

  26. Tuncbag, N., Kar, G., Gursoy, A., Keskin, O. & Nussinov, R. Towards inferring time dimensionality in protein-protein interaction networks by integrating structures: the p53 example. Mol. Biosyst. 5, 1770–1778 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Kar, G., Keskin, O., Gursoy, A. & Nussinov, R. Allostery and population shift in drug discovery. Curr. Opin. Pharmacol. 10, 715–7122 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Acuner Ozbabacan, S.E., Gursoy, A., Keskin, O. & Nussinov, R. Conformational ensembles, signal transduction and residue hot spots: application to drug discovery. Curr. Opin. Drug. Discov. Devel. 13, 527–537 (2010).

    PubMed  Google Scholar 

  29. Keskin, O. & Nussinov, R. Favorable scaffolds: proteins with different sequence, structure and function may associate in similar ways. Protein Eng. Des. Sel. 18, 11–24 (2005).

    Article  CAS  PubMed  Google Scholar 

  30. Tuncbag, N., Gursoy, A., Guney, E., Nussinov, R. & Keskin, O. Architectures and functional coverage of protein-protein interfaces. J. Mol. Biol. 381, 785–802 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Shatsky, M., Nussinov, R. & Wolfson, H.J. A method for simultaneous alignment of multiple protein structures. Proteins 56, 143–156 (2004).

    Article  CAS  PubMed  Google Scholar 

  32. Mashiach, E., Nussinov, R. & Wolfson, H.J. FiberDock: flexible induced-fit backbone refinement in molecular docking. Proteins 78, 1503–1519 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Aloy, P. & Russell, R.B. Interrogating protein interaction networks through structural biology. Proc. Natl Acad. Sci. USA 99, 5896–5901 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Kundrotas, P.J., Lensink, M.F. & Alexov, E. Homology-based modeling of 3D structures of protein-protein complexes using alignments of modified sequence profiles. Int. J. Biol. Macromol. 43, 198–208 (2008).

    Article  CAS  PubMed  Google Scholar 

  35. Lu, L., Lu, H. & Skolnick, J. MULTIPROSPECTOR: an algorithm for the prediction of protein-protein interactions by multimeric threading. Proteins 49, 350–364 (2002).

    Article  CAS  PubMed  Google Scholar 

  36. Martin, J. Beauty is in the eye of the beholder: proteins can recognize binding sites of homologous proteins in more than one way. PLoS Comput. Biol. 6, e1000821 (2010).

    Article  PubMed  PubMed Central  Google Scholar 

  37. Gunther, S., May, P., Hoppe, A., Frommel, C. & Preissner, R. Docking without docking: ISEARCH—prediction of interactions using known interfaces. Proteins 69, 839–844 (2007).

    Article  PubMed  Google Scholar 

  38. Sinha, R., Kundrotas, P.J. & Vakser, I.A. Docking by structural similarity at protein-protein interfaces. Proteins 78, 3235–3241 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Kundrotas, P.J. & Vakser, I.A. Accuracy of protein-protein binding sites in high-throughput template-based modeling. PLoS Comput. Biol. 6, e1000727 (2010).

    Article  PubMed  PubMed Central  Google Scholar 

  40. Xie, L. & Bourne, P.E. Functional coverage of the human genome by existing structures, structural genomics targets, and homology models. PLoS Comput. Biol. 1, e31 (2005).

    Article  PubMed  PubMed Central  Google Scholar 

  41. Xie, L., Xie, L. & Bourne, P.E. Structure-based systems biology for analyzing off-target binding. Curr. Opin. Struct. Biol. 21, 189–199 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Bradford, J.R. & Westhead, D.R. Improved prediction of protein-protein binding sites using a support vector machines approach. Bioinformatics 21, 1487–1494 (2005).

    Article  CAS  PubMed  Google Scholar 

  43. Liang, S., Zhang, C., Liu, S. & Zhou, Y. Protein binding site prediction using an empirical scoring function. Nucleic Acids Res. 34, 3698–3707 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. Wells, J.A. Systematic mutational analyses of protein-protein interfaces. Methods Enzymol. 202, 390–411 (1991).

    Article  CAS  PubMed  Google Scholar 

  45. Pearson, W.R. & Lipman, D.J. Improved tools for biological sequence comparison. Proc. Natl Acad. Sci. USA 85, 2444–2448 (1988).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. Hubbard, S.J. & Thornton, J.M. Naccess (Department of Biochemistry and Molecular Biology, University College, London, 1993).

  47. Hwang, H., Pierce, B., Mintseris, J., Janin, J. & Weng, Z. Protein-protein docking benchmark version 3.0. Proteins 73, 705–709 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  48. Tuncbag, N., Keskin, O. & Gursoy, A. HotPoint: hot spot prediction server for protein interfaces. Nucleic Acids Res. 38 (Suppl): W402–W406 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  49. Tuncbag, N., Gursoy, A. & Keskin, O. Identification of computational hot spots in protein interfaces: combining solvent accessibility and inter-residue potentials improves the accuracy. Bioinformatics 25, 1513–1520 (2009).

    Article  CAS  PubMed  Google Scholar 

  50. Fischer, T.B. et al. The binding interface database (BID): a compilation of amino acid hot spots in protein interfaces. Bioinformatics 19, 1453–1454 (2003).

    Article  CAS  PubMed  Google Scholar 

  51. Thorn, K.S. & Bogan, A.A. ASEdb: a database of alanine mutations and their effects on the free energy of binding in protein interactions. Bioinformatics 17, 284–285 (2001).

    Article  CAS  PubMed  Google Scholar 

  52. MacKerell, A.D. et al. All-atom empirical potential for molecular modeling and dynamics studies of proteins. J. Phys. Chem. B 102, 3586–3616 (1998).

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgements

We thank all members of the Koc University Computational Systems Biology group, especially C. Ulubas, A. Selim Aytuna and U. Ogmen (former PRISM development team). We thank former and current members of the Tel Aviv University Structural Bioinformatics group, particularly M. Shatsky (MultiProt) and E. Mashiach (FiberDock). This work has been supported by TUBITAK (Research Grant numbers: 109T343 and 109E207). This project has been funded in whole or in part with federal funds from the National Cancer Institute, US National Institutes of Health (contract number HHSN261200800001E). The content of this publication does not necessarily reflect the views or policies of the Department of Health and Human Services, nor does mention of trade names, commercial products or organizations imply endorsement by the U.S. Government. This research was supported (in part) by the Intramural Research Program of the National Institutes of Health, National Cancer Institute, Center for Cancer Research. O.K. acknowledges support from the Turkish Academy of Sciences (TUBA).

Author information

Authors and Affiliations

  1. Center for Computational Biology and Bioinformatics, College of Engineering, Koc University, Rumelifeneri Yolu, Sariyer Istanbul, Turkey

    Nurcan Tuncbag, Attila Gursoy & Ozlem Keskin

  2. Basic Science Program, SAIC-Frederick Inc., Center for Cancer Research Nanobiology Program, NCI-Frederick, Frederick, Maryland, USA

    Ruth Nussinov

  3. Department of Human Genetics and Molecular Medicine, Sackler Institute of Molecular Medicine, Sackler School of Medicine, Tel Aviv University, Tel Aviv, Israel

    Ruth Nussinov

Authors
  1. Nurcan Tuncbag
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Attila Gursoy
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Ruth Nussinov
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Ozlem Keskin
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

A.G. and O.K. developed the initial PRISM concept. N.T., A.G., R.N. and O.K. contributed substantially to the design and implementation of the current flexible PRISM. N.T. did coding and wrote the initial manuscript. All authors contributed substantially to the discussion of the results and to the writing of the paper.

Corresponding authors

Correspondence to Attila Gursoy or Ozlem Keskin.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Tuncbag, N., Gursoy, A., Nussinov, R. et al. Predicting protein-protein interactions on a proteome scale by matching evolutionary and structural similarities at interfaces using PRISM. Nat Protoc 6, 1341–1354 (2011). https://doi.org/10.1038/nprot.2011.367

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/nprot.2011.367

This article is cited by

Comments

By submitting a comment you agree to abide by our Terms and Community Guidelines. If you find something abusive or that does not comply with our terms or guidelines please flag it as inappropriate.

Search

Advanced search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing