Skip to main content
NCBI home page
Comparative and Functional Genomics logoLink to Comparative and Functional Genomics
. 2003 Jul;4(4):420–423. doi: 10.1002/cfg.309

In Silico Identification of Functional Protein Interfaces

Rachel E Bell 1, Nir Ben-Tal 1,✉
PMCID: PMC2447364  PMID: 18629079

Abstract

Proteins perform many of their biological roles through protein–protein, protein–DNA or protein–ligand interfaces. The identification of the amino acids comprising these interfaces often enhances our understanding of the biological function of the proteins. Many methods for the detection of functional interfaces have been developed, and large-scale analyses have provided assessments of their accuracy. Among them are those that consider the size of the protein interface, its amino acid composition and its physicochemical and geometrical properties. Other methods to this effect use statistical potential functions of pairwise interactions, and evolutionary information. The rationale of the evolutionary approach is that functional and structural constraints impose selective pressure; hence, biologically important interfaces often evolve at a slower pace than do other external regions of the protein. Recently, an algorithm, Rate4Site, and a web-server, ConSurf (http://consurf.tau.ac.il/), for the identification of functional interfaces based on the evolutionary relations among homologous proteins as reflected in phylogenetic trees, were developed in our laboratory. The explicit use of the tree topology and branch lengths makes the method remarkably accurate and sensitive. Here we demonstrate its potency in the identification of the functional interfaces of a hypothetical protein, the structure of which was determined as part of the international structural genomics effort. Finally, we propose to combine complementary procedures, in order to enhance the overall performance of methods for the identification of functional interfaces in proteins.

Full Text

The Full Text of this article is available as a PDF (183.5 KB).

Selected References

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

  1. Aloy P., Querol E., Aviles F. X., Sternberg M. J. Automated structure-based prediction of functional sites in proteins: applications to assessing the validity of inheriting protein function from homology in genome annotation and to protein docking. J Mol Biol. 2001 Aug 10;311(2):395–408. doi: 10.1006/jmbi.2001.4870. [DOI] [PubMed] [Google Scholar]
  2. Altschul S. F., Madden T. L., Schäffer A. A., Zhang J., Zhang Z., Miller W., Lipman D. J. Gapped BLAST and PSI-BLAST: a new generation of protein database search programs. Nucleic Acids Res. 1997 Sep 1;25(17):3389–3402. doi: 10.1093/nar/25.17.3389. [DOI] [PMC free article] [PubMed] [Google Scholar]
  3. Armon A., Graur D., Ben-Tal N. ConSurf: an algorithmic tool for the identification of functional regions in proteins by surface mapping of phylogenetic information. J Mol Biol. 2001 Mar 16;307(1):447–463. doi: 10.1006/jmbi.2000.4474. [DOI] [PubMed] [Google Scholar]
  4. Blouin Christian, Boucher Yan, Roger Andrew J. Inferring functional constraints and divergence in protein families using 3D mapping of phylogenetic information. Nucleic Acids Res. 2003 Jan 15;31(2):790–797. doi: 10.1093/nar/gkg151. [DOI] [PMC free article] [PubMed] [Google Scholar]
  5. Boeckmann Brigitte, Bairoch Amos, Apweiler Rolf, Blatter Marie-Claude, Estreicher Anne, Gasteiger Elisabeth, Martin Maria J., Michoud Karine, O'Donovan Claire, Phan Isabelle. The SWISS-PROT protein knowledgebase and its supplement TrEMBL in 2003. Nucleic Acids Res. 2003 Jan 1;31(1):365–370. doi: 10.1093/nar/gkg095. [DOI] [PMC free article] [PubMed] [Google Scholar]
  6. Dean A. M., Golding G. B. Enzyme evolution explained (sort of). Pac Symp Biocomput. 2000:6–17. doi: 10.1142/9789814447331_0002. [DOI] [PubMed] [Google Scholar]
  7. Elcock A. H., McCammon J. A. Identification of protein oligomerization states by analysis of interface conservation. Proc Natl Acad Sci U S A. 2001 Mar 6;98(6):2990–2994. doi: 10.1073/pnas.061411798. [DOI] [PMC free article] [PubMed] [Google Scholar]
  8. Fleming Melissa A., Potter John D., Ramirez Christina J., Ostrander Gary K., Ostrander Elaine A. Understanding missense mutations in the BRCA1 gene: an evolutionary approach. Proc Natl Acad Sci U S A. 2003 Jan 16;100(3):1151–1156. doi: 10.1073/pnas.0237285100. [DOI] [PMC free article] [PubMed] [Google Scholar]
  9. Gaucher E. A., Miyamoto M. M., Benner S. A. Function-structure analysis of proteins using covarion-based evolutionary approaches: Elongation factors. Proc Natl Acad Sci U S A. 2001 Jan 16;98(2):548–552. doi: 10.1073/pnas.98.2.548. [DOI] [PMC free article] [PubMed] [Google Scholar]
  10. Glaser Fabian, Pupko Tal, Paz Inbal, Bell Rachel E., Bechor-Shental Dalit, Martz Eric, Ben-Tal Nir. ConSurf: identification of functional regions in proteins by surface-mapping of phylogenetic information. Bioinformatics. 2003 Jan;19(1):163–164. doi: 10.1093/bioinformatics/19.1.163. [DOI] [PubMed] [Google Scholar]
  11. Henikoff S., Henikoff J. G. Automated assembly of protein blocks for database searching. Nucleic Acids Res. 1991 Dec 11;19(23):6565–6572. doi: 10.1093/nar/19.23.6565. [DOI] [PMC free article] [PubMed] [Google Scholar]
  12. Hu Z., Ma B., Wolfson H., Nussinov R. Conservation of polar residues as hot spots at protein interfaces. Proteins. 2000 Jun 1;39(4):331–342. [PubMed] [Google Scholar]
  13. Janin J., Rodier F. Protein-protein interaction at crystal contacts. Proteins. 1995 Dec;23(4):580–587. doi: 10.1002/prot.340230413. [DOI] [PubMed] [Google Scholar]
  14. Janin J. Specific versus non-specific contacts in protein crystals. Nat Struct Biol. 1997 Dec;4(12):973–974. doi: 10.1038/nsb1297-973. [DOI] [PubMed] [Google Scholar]
  15. Jones S., Thornton J. M. Analysis of protein-protein interaction sites using surface patches. J Mol Biol. 1997 Sep 12;272(1):121–132. doi: 10.1006/jmbi.1997.1234. [DOI] [PubMed] [Google Scholar]
  16. Landgraf R., Xenarios I., Eisenberg D. Three-dimensional cluster analysis identifies interfaces and functional residue clusters in proteins. J Mol Biol. 2001 Apr 13;307(5):1487–1502. doi: 10.1006/jmbi.2001.4540. [DOI] [PubMed] [Google Scholar]
  17. Lichtarge Olivier, Sowa Mathew E. Evolutionary predictions of binding surfaces and interactions. Curr Opin Struct Biol. 2002 Feb;12(1):21–27. doi: 10.1016/s0959-440x(02)00284-1. [DOI] [PubMed] [Google Scholar]
  18. Lijnzaad P., Argos P. Hydrophobic patches on protein subunit interfaces: characteristics and prediction. Proteins. 1997 Jul;28(3):333–343. [PubMed] [Google Scholar]
  19. Lockless S. W., Ranganathan R. Evolutionarily conserved pathways of energetic connectivity in protein families. Science. 1999 Oct 8;286(5438):295–299. doi: 10.1126/science.286.5438.295. [DOI] [PubMed] [Google Scholar]
  20. Madabushi Srinivasan, Yao Hui, Marsh Mike, Kristensen David M., Philippi Anne, Sowa Mathew E., Lichtarge Olivier. Structural clusters of evolutionary trace residues are statistically significant and common in proteins. J Mol Biol. 2002 Feb 8;316(1):139–154. doi: 10.1006/jmbi.2001.5327. [DOI] [PubMed] [Google Scholar]
  21. Moont G., Gabb H. A., Sternberg M. J. Use of pair potentials across protein interfaces in screening predicted docked complexes. Proteins. 1999 May 15;35(3):364–373. [PubMed] [Google Scholar]
  22. Ofran Yanay, Rost Burkhard. Analysing six types of protein-protein interfaces. J Mol Biol. 2003 Jan 10;325(2):377–387. doi: 10.1016/s0022-2836(02)01223-8. [DOI] [PubMed] [Google Scholar]
  23. Pazos F., Helmer-Citterich M., Ausiello G., Valencia A. Correlated mutations contain information about protein-protein interaction. J Mol Biol. 1997 Aug 29;271(4):511–523. doi: 10.1006/jmbi.1997.1198. [DOI] [PubMed] [Google Scholar]
  24. Pazos F., Valencia A. Similarity of phylogenetic trees as indicator of protein-protein interaction. Protein Eng. 2001 Sep;14(9):609–614. doi: 10.1093/protein/14.9.609. [DOI] [PubMed] [Google Scholar]
  25. Pazos Florencio, Valencia Alfonso. In silico two-hybrid system for the selection of physically interacting protein pairs. Proteins. 2002 May 1;47(2):219–227. doi: 10.1002/prot.10074. [DOI] [PubMed] [Google Scholar]
  26. Ponstingl H., Henrick K., Thornton J. M. Discriminating between homodimeric and monomeric proteins in the crystalline state. Proteins. 2000 Oct 1;41(1):47–57. doi: 10.1002/1097-0134(20001001)41:1<47::aid-prot80>3.3.co;2-#. [DOI] [PubMed] [Google Scholar]
  27. Sheinerman F. B., Norel R., Honig B. Electrostatic aspects of protein-protein interactions. Curr Opin Struct Biol. 2000 Apr;10(2):153–159. doi: 10.1016/s0959-440x(00)00065-8. [DOI] [PubMed] [Google Scholar]
  28. Simon Alexander L., Stone Eric A., Sidow Arend. Inference of functional regions in proteins by quantification of evolutionary constraints. Proc Natl Acad Sci U S A. 2002 Mar 5;99(5):2912–2917. doi: 10.1073/pnas.042692299. [DOI] [PMC free article] [PubMed] [Google Scholar]
  29. Thompson J. D., Higgins D. G., Gibson T. J. CLUSTAL W: improving the sensitivity of progressive multiple sequence alignment through sequence weighting, position-specific gap penalties and weight matrix choice. Nucleic Acids Res. 1994 Nov 11;22(22):4673–4680. doi: 10.1093/nar/22.22.4673. [DOI] [PMC free article] [PubMed] [Google Scholar]
  30. 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. 2001 Mar;17(3):284–285. doi: 10.1093/bioinformatics/17.3.284. [DOI] [PubMed] [Google Scholar]
  31. Tsai C. J., Lin S. L., Wolfson H. J., Nussinov R. Studies of protein-protein interfaces: a statistical analysis of the hydrophobic effect. Protein Sci. 1997 Jan;6(1):53–64. doi: 10.1002/pro.5560060106. [DOI] [PMC free article] [PubMed] [Google Scholar]
  32. Valdar W. S., Thornton J. M. Conservation helps to identify biologically relevant crystal contacts. J Mol Biol. 2001 Oct 19;313(2):399–416. doi: 10.1006/jmbi.2001.5034. [DOI] [PubMed] [Google Scholar]
  33. Valdar William S. J. Scoring residue conservation. Proteins. 2002 Aug 1;48(2):227–241. doi: 10.1002/prot.10146. [DOI] [PubMed] [Google Scholar]
  34. Xenarios Ioannis, Salwínski Lukasz, Duan Xiaoqun Joyce, Higney Patrick, Kim Sul-Min, Eisenberg David. DIP, the Database of Interacting Proteins: a research tool for studying cellular networks of protein interactions. Nucleic Acids Res. 2002 Jan 1;30(1):303–305. doi: 10.1093/nar/30.1.303. [DOI] [PMC free article] [PubMed] [Google Scholar]
  35. Yao Hui, Kristensen David M., Mihalek Ivana, Sowa Mathew E., Shaw Chad, Kimmel Marek, Kavraki Lydia, Lichtarge Olivier. An accurate, sensitive, and scalable method to identify functional sites in protein structures. J Mol Biol. 2003 Feb 7;326(1):255–261. doi: 10.1016/s0022-2836(02)01336-0. [DOI] [PubMed] [Google Scholar]

Articles from Comparative and Functional Genomics are provided here courtesy of Wiley

RESOURCES