Abstract
Proteins use their functional regions to exploit various activities, including binding to other proteins, nucleic acids, or drugs. Functional sites of the proteins have a tendency to be more conserved than the rest of the protein surface. Therefore, detection of the conserved residues using phylogenetic analysis is a general approach to predict functionally critical residues. In this chapter, we describe some of the available methods to predict functional sites and demonstrate a complete pipeline with tool alternatives at several steps. We explain the standard procedure and all intermediate stages including homology detection with BLAST search, multiple sequence alignment (MSA) and the construction of a phylogenetic tree for a given query sequence. Additionally, we demonstrate the prediction results of these methods on a case study. Finally, we discuss the possible challenges and bottlenecks throughout the pipeline. Our step-by-step description about the functional site prediction could be a helpful resource for the researchers interested in finding protein functional sites, to be used in drug discovery research.
Access this chapter
Tax calculation will be finalised at checkout
Purchases are for personal use only
References
The UniProt Consortium (2017) UniProt: the universal protein knowledgebase. Nucleic Acids Res 45:D158–D169. https://doi.org/10.1093/nar/gkw1152
Keskin O, Tuncbag N, Gursoy A (2016) Predicting protein-protein interactions from the molecular to the proteome level. Chem Rev 116:4884–4909. https://doi.org/10.1021/acs.chemrev.5b00683
Pazos F, Bang J-W (2006) Computational prediction of functionally important regions in proteins. Curr Bioinforma 1:15–23. https://doi.org/10.2174/157489306775330633
Capra JA, Singh M (2007) Predicting functionally important residues from sequence conservation. Bioinformatics 23:1875–1882. https://doi.org/10.1093/bioinformatics/btm270
Keskin O, Tsai C-J, Wolfson H, Nussinov R (2004) A new, structurally nonredundant, diverse data set of protein-protein interfaces and its implications. Protein Sci 13:1043–1055. https://doi.org/10.1110/ps.03484604
Tuncbag N, Gursoy A, Guney E et al (2008) Architectures and functional coverage of protein–protein interfaces. J Mol Biol 381:785–802. https://doi.org/10.1016/j.jmb.2008.04.071
Bray T, Chan P, Bougouffa S et al (2009) SitesIdentify: a protein functional site prediction tool. BMC Bioinformatics 10:379. https://doi.org/10.1186/1471-2105-10-379
Kc DB, Livesay DR (2011) Topology improves phylogenetic motif functional site predictions. IEEE/ACM Trans Comput Biol Bioinform 8:226–233. https://doi.org/10.1109/TCBB.2009.60
Pazos F, Valencia A (2001) Similarity of phylogenetic trees as indicator of protein-protein interaction. Protein Eng 14:609–614. https://doi.org/10.1093/protein/14.9.609
Lichtarge O, Bourne HR, Cohen FE (1996) An evolutionary trace method defines binding surfaces common to protein families. J Mol Biol 257:342–358. https://doi.org/10.1006/jmbi.1996.0167
Landau M, Mayrose I, Rosenberg Y et al (2005) ConSurf 2005: the projection of evolutionary conservation scores of residues on protein structures. Nucleic Acids Res 33:W299–W302. https://doi.org/10.1093/nar/gki370
Ashkenazy H, Abadi S, Martz E et al (2016) ConSurf 2016: an improved methodology to estimate and visualize evolutionary conservation in macromolecules. Nucleic Acids Res 44:W344–W350. https://doi.org/10.1093/nar/gkw408
Sankararaman S, Sjölander K (2008) INTREPID--INformation-theoretic TREe traversal for protein functional site IDentification. Bioinformatics 24:2445–2452. https://doi.org/10.1093/bioinformatics/btn474
Lua RC, Wilson SJ, Konecki DM et al (2016) UET: a database of evolutionarily-predicted functional determinants of protein sequences that cluster as functional sites in protein structures. Nucleic Acids Res 44:D308–D312. https://doi.org/10.1093/nar/gkv1279
Ofran Y, Rost B (2007) ISIS: interaction sites identified from sequence. Bioinformatics 23:e13–e16. https://doi.org/10.1093/bioinformatics/btl303
de Juan D, Pazos F, Valencia A (2013) Emerging methods in protein co-evolution. Nat Rev Genet 14:249–261. https://doi.org/10.1038/nrg3414
Hopf TA, Schärfe CPI, Rodrigues JPGLM et al (2014) Sequence co-evolution gives 3D contacts and structures of protein complexes. eLife 3:1–45. https://doi.org/10.7554/eLife.03430
Rodriguez-Rivas J, Marsili S, Juan D, Valencia A (2016) Conservation of coevolving protein interfaces bridges prokaryote-eukaryote homologies in the twilight zone. Proc Natl Acad Sci U S A 113:15018–15023. https://doi.org/10.1073/pnas.1611861114
Gueudré T, Baldassi C, Zamparo M et al (2016) Simultaneous identification of specifically interacting paralogs and interprotein contacts by direct coupling analysis. Proc Natl Acad Sci U S A 113:12186–12191. https://doi.org/10.1073/pnas.1607570113
Baker FN, Porollo A (2016) CoeViz: a web-based tool for coevolution analysis of protein residues. BMC Bioinformatics 17:119. https://doi.org/10.1186/s12859-016-0975-z
Huntley RP, Sawford T, Mutowo-Meullenet P et al (2015) The GOA database: gene ontology annotation updates for 2015. Nucleic Acids Res 43:D1057–D1063. https://doi.org/10.1093/nar/gku1113
Berezin C, Glaser F, Rosenberg J et al (2004) ConSeq: the identification of functionally and structurally important residues in protein sequences. Bioinformatics 20:1322–1324. https://doi.org/10.1093/bioinformatics/bth070
Acknowledgements
H.A. acknowledges TUBITAK 2211 Doctoral Fellowship Program. N.T. thanks to the TUBITAK Career Development Program (Project no: 117E192). T.D. acknowledges TUBITAK BIDEB 2218 Program.
Author information
Authors and Affiliations
Corresponding author
Editor information
Editors and Affiliations
Rights and permissions
Copyright information
© 2018 Springer Science+Business Media, LLC, part of Springer Nature
About this protocol
Cite this protocol
Atas, H., Tuncbag, N., Doğan, T. (2018). Phylogenetic and Other Conservation-Based Approaches to Predict Protein Functional Sites. In: Gore, M., Jagtap, U. (eds) Computational Drug Discovery and Design. Methods in Molecular Biology, vol 1762. Humana Press, New York, NY. https://doi.org/10.1007/978-1-4939-7756-7_4
Download citation
DOI: https://doi.org/10.1007/978-1-4939-7756-7_4
Published:
Publisher Name: Humana Press, New York, NY
Print ISBN: 978-1-4939-7755-0
Online ISBN: 978-1-4939-7756-7
eBook Packages: Springer Protocols