Abstract
Comparative protein structure modeling is a computational approach to build three-dimensional structural models for proteins using experimental structures of related protein family members as templates. Regular blind assessments of modeling accuracy have demonstrated that comparative protein structure modeling is currently the most reliable technique to model protein structures. Homology models are often sufficiently accurate to substitute for experimental structures in a wide variety of applications. Since the usefulness of a model for specific application is determined by its accuracy, model quality estimation is an essential component of protein structure prediction. Comparative protein modeling has become a routine approach in many areas of life science research since fully automated modeling systems allow also nonexperts to build reliable models. In this chapter, we describe practical approaches for automated protein structure modeling with SWISS-MODEL Workspace and the Protein Model Portal.
Access this chapter
Tax calculation will be finalised at checkout
Purchases are for personal use only
References
Schwede, T., A. Sali, N. Eswar, and M.C. Peitsch, Protein Structure Modeling., in Computational Structural Biology, T. Schwede and M.C. Peitsch, Editors. 2008, World Scientific Singapore. p. 3–35.
Baker, D. and A. Sali. (2001) Protein structure prediction and structural genomics. Science. 294, 93–96.
Sali, A. and T.L. Blundell. (1993) Comparative protein modeling by satisfaction of spatial restraints. J Mol Biol. 234, 779–815.
Sutcliffe, M.J., I. Haneef, D. Carney, and T.L. Blundell. (1987) Knowledge based modeling of homologous proteins, Part I: Three-dimensional frameworks derived from the simultaneous superposition of multiple structures. Protein Eng. 1, 377–384.
Peitsch, M.C. (1996) ProMod and Swiss-Model: Internet-based tools for automated comparative protein modeling. Biochem Soc Trans. 24, 274–279.
Fiser, A. Template-based protein structure modeling. Methods Mol Biol. 673, 73–94.
Moult, J. (2005) A decade of CASP: progress, bottlenecks and prognosis in protein structure prediction. Curr Opin Struct Biol. 15, 285–289.
Arinaminpathy, Y., E. Khurana, D.M. Engelman, and M.B. Gerstein. (2009) Computational analysis of membrane proteins: the largest class of drug targets. Drug Discov Today. 14, 1130–1135.
Schwede, T., A. Sali, B. Honig, M. Levitt, et al. (2009) Outcome of a workshop on applications of protein models in biomedical research. Structure. 17, 151–159.
Peitsch, M.C. (2002) About the use of protein models. Bioinformatics. 18, 934–938.
Tramontano, A., The biological applications of protein models., in Computational Structural Biology, T. Schwede and M.C. Peitsch, Editors. 2008, World Scientific Publishing. p. 111–127.
Junne, T., T. Schwede, V. Goder, and M. Spiess. (2006) The plug domain of yeast Sec61p is important for efficient protein translocation, but is not essential for cell viability. Mol Biol Cell. 17, 4063–4068.
Grant, M.A. (2009) Protein structure prediction in structure-based ligand design and virtual screening. Comb Chem High Throughput Screen. 12, 940–960.
Takeda-Shitaka, M., D. Takaya, C. Chiba, H. Tanaka, et al. (2004) Protein structure prediction in structure based drug design. Curr Med Chem. 11, 551–558.
Das, R. and D. Baker. (2009) Prospects for de novo phasing with de novo protein models. Acta Crystallogr D Biol Crystallogr. 65, 169–175.
Giorgetti, A., D. Raimondo, A.E. Miele, and A. Tramontano. (2005) Evaluating the usefulness of protein structure models for molecular replacement. Bioinformatics. 21 Suppl 2, ii72–76.
Topf, M., M.L. Baker, M.A. Marti-Renom, W. Chiu, et al. (2006) Refinement of protein structures by iterative comparative modeling and CryoEM density fitting. J Mol Biol. 357, 1655–1668.
Topf, M. and A. Sali. (2005) Combining electron microscopy and comparative protein structure modeling. Curr Opin Struct Biol. 15, 578–585.
Zhu, J., L. Cheng, Q. Fang, Z.H. Zhou, et al. Building and refining protein models within cryo-electron microscopy density maps based on homology modeling and multiscale structure refinement. J Mol Biol. 397, 835–851.
Guex, N., M.C. Peitsch, and T. Schwede. (2009) Automated comparative protein structure modeling with SWISS-MODEL and Swiss-PdbViewer: a historical perspective. Electrophoresis. 30 Suppl 1, S162–173.
Brazas, M.D., J.T. Yamada, and B.F. Ouellette. (2010) Providing web servers and training in Bioinformatics: 2010 update on the Bioinformatics Links Directory. Nucleic Acids Res. 38 Suppl, W3–6.
Battey, J.N., J. Kopp, L. Bordoli, R.J. Read, et al. (2007) Automated server predictions in CASP7. Proteins. 69, 68–82.
Pieper, U., B.M. Webb, D.T. Barkan, D. Schneidman-Duhovny, et al. (2011) ModBase, a database of annotated comparative protein structure models, and associated resources. Nucleic Acids Res. 39, D465–474.
Chivian, D. and D. Baker. (2006) Homology modeling using parametric alignment ensemble generation with consensus and energy-based model selection. Nucleic Acids Res. 34, e112.
Hildebrand, A., M. Remmert, A. Biegert, and J. Soding. (2009) Fast and accurate automatic structure prediction with HHpred. Proteins. 77 Suppl 9, 128–132.
Zhang, Y. (2008) I-TASSER server for protein 3D structure prediction. BMC Bioinformatics. 9, 40.
Larsson, P., M.J. Skwark, B. Wallner, and A. Elofsson. Improved predictions by Pcons.net using multiple templates. Bioinformatics. 27, 426–427.
Kelley, L.A. and M.J. Sternberg. (2009) Protein structure prediction on the Web: a case study using the Phyre server. Nat Protoc. 4, 363–371.
Fernandez-Fuentes, N., C.J. Madrid-Aliste, B.K. Rai, J.E. Fajardo, et al. (2007) M4T: a comparative protein structure modeling server. Nucleic Acids Res. 35, W363–368.
Schneidman-Duhovny, D., M. Hammel, and A. Sali. (2011) Macromolecular docking restrained by a small angle X-ray scattering profile.J Struct Biol 173, 461–471.
Vroling, B., M. Sanders, C. Baakman, A. Borrmann, et al. GPCRDB: information system for G protein-coupled receptors. Nucleic Acids Res. 39, D309–319.
Zhang, Y., M.E. Devries, and J. Skolnick. (2006) Structure modeling of all identified G protein-coupled receptors in the human genome. PLoS Comput Biol. 2, e13.
Marcatili, P., A. Rosi, and A. Tramontano. (2008) PIGS: automatic prediction of antibody structures. Bioinformatics. 24, 1953–1954.
Sivasubramanian, A., A. Sircar, S. Chaudhury, and J.J. Gray. (2009) Toward high-resolution homology modeling of antibody Fv regions and application to antibody-antigen docking. Proteins. 74, 497–514.
Schwede, T., A. Diemand, N. Guex, and M.C. Peitsch. (2000) Protein structure computing in the genomic era. Res Microbiol. 151, 107–112.
Kiefer, F., K. Arnold, M. Kunzli, L. Bordoli, et al. (2009) The SWISS-MODEL Repository and associated resources. Nucleic Acids Res. 37, D387–392.
Pieper, U., B.M. Webb, D.T. Barkan, D. Schneidman-Duhovny, et al. (2011) ModBase, a database of annotated comparative protein structure models, and associated resources. Nucleic Acids Res 39, D465–D474.
Koh, I.Y., V.A. Eyrich, M.A. Marti-Renom, D. Przybylski, et al. (2003) EVA: Evaluation of protein structure prediction servers. Nucleic Acids Res. 31, 3311–3315.
Chothia, C. and A.M. Lesk. (1986) The relation between the divergence of sequence and structure in proteins. Embo J. 5, 823–826.
Peng, J. and J. Xu. (2010) Low-homology protein threading. Bioinformatics. 26, i294–300.
Benkert, P., S.C. Tosatto, and T. Schwede. (2009) Global and local model quality estimation at CASP8 using the scoring functions QMEAN and QMEANclust. Proteins. 77 Suppl 9, 173–180.
McGuffin, L.J. and D.B. Roche. (2010) Rapid model quality assessment for protein structure predictions using the comparison of multiple models without structural alignments. Bioinformatics. 26, 182–188.
Eramian, D., N. Eswar, M.Y. Shen, and A. Sali. (2008) How well can the accuracy of comparative protein structure models be predicted? Protein Sci. 17, 1881–1893.
Melo, F. and E. Feytmans, Scoring Functions for Protein Structure Prediction. Computational Structural Biology, ed. T. Schwede and M.C. Peitsch. 2008: World Scientific Publishing.
Zhou, H. and Y. Zhou. (2002) Distance-scaled, finite ideal-gas reference state improves structure-derived potentials of mean force for structure selection and stability prediction. Protein Sci. 11, 2714–2726.
Guex, N. and M.C. Peitsch. (1997) SWISS-MODEL and the Swiss-PdbViewer: an environment for comparative protein modeling. Electrophoresis. 18, 2714–2723.
Arnold, K., L. Bordoli, J. Kopp, and T. Schwede. (2006) The SWISS-MODEL workspace: a web-based environment for protein structure homology modeling. Bioinformatics. 22, 195–201.
Zhang, Y. and J. Skolnick. (2005) The protein structure prediction problem could be solved using the current PDB library. Proc Natl Acad Sci U S A. 102, 1029–1034.
Peitsch, M.C. (1995) Protein modeling by E-Mail. BioTechnology. 13, 658–660.
van Gunsteren, W.F., S.R. Billeter, A.A. Eising, P.H. Hünenberger, et al., Biomolecular Simulations: The GROMOS96 Manual and User Guide. 1996, Zürich: VdF Hochschulverlag ETHZ.
Benkert, P., M. Kunzli, and T. Schwede. (2009) QMEAN server for protein model quality estimation. Nucleic Acids Res. 37, W510–514.
Arnold, K., F. Kiefer, J. Kopp, J.N. Battey, et al. (2009) The Protein Model Portal. J Struct Funct Genomics. 10, 1–8.
Berman, H.M., J.D. Westbrook, M.J. Gabanyi, W. Tao, et al. (2009) The protein structure initiative structural genomics knowledgebase. Nucleic Acids Res. 37, D365–368.
Berman, H., K. Henrick, H. Nakamura, and J.L. Markley. (2007) The worldwide Protein Data Bank (wwPDB): ensuring a single, uniform archive of PDB data. Nucleic Acids Res. 35, D301–303.
Pieper, U., B.M. Webb, D.T. Barkan, D. Schneidman-Duhovny, et al. (2011) ModBase, a database of annotated comparative protein structure models, and associated resources. Nucleic Acids Res. D465–474.
Roy, A., A. Kucukural, and Y. Zhang. (2010) I-TASSER: a unified platform for automated protein structure and function prediction. Nat Protoc. 5, 725–738.
Ginalski, K., A. Elofsson, D. Fischer, and L. Rychlewski. (2003) 3D-Jury: a simple approach to improve protein structure predictions. Bioinformatics. 19, 1015–1018.
McGuffin, L.J. (2008) The ModFOLD server for the quality assessment of protein structural models. Bioinformatics. 24, 586–587.
Hartshorn, M.J. (2002) AstexViewer: a visualisation aid for structure-based drug design. J Comput Aided Mol Des. 16, 871–881.
Mulder, N. and R. Apweiler. (2007) InterPro and InterProScan: tools for protein sequence classification and comparison. Methods Mol Biol. 396, 59–70.
Jones, D.T. (1999) Protein secondary structure prediction based on position-specific scoring matrices. J Mol Biol. 292, 195–202.
Jones, D.T. and J.J. Ward. (2003) Prediction of disordered regions in proteins from position specific score matrices. Proteins. 53 Suppl 6, 573–578.
Jones, D.T. (2007) Improving the accuracy of transmembrane protein topology prediction using evolutionary information. Bioinformatics. 23, 538–544.
Altschul, S.F., T.L. Madden, A.A. Schaffer, J. Zhang, et al. (1997) Gapped BLAST and PSI-BLAST: a new generation of protein database search programs. Nucleic Acids Res. 25, 3389–3402.
Soding, J. (2005) Protein homology detection by HMM-HMM comparison. Bioinformatics. 21, 951–960.
Hooft, R.W., G. Vriend, C. Sander, and E.E. Abola. (1996) Errors in protein structures. Nature. 381, 272.
Laskowski, R.A., M.W. MacArthur, D.S. Moss, and J.M. Thornton. (1993) PROCHECK: a program to check the stereochemical quality of protein structures. J Appl Cryst. 26, 283–291.
Kabsch, W. and C. Sander. (1983) Dictionary of protein secondary structure: pattern recognition of hydrogen-bonded and geometrical features. Biopolymers. 22, 2577–2637.
Hutchinson, E.G. and J.M. Thornton. (1996) PROMOTIF - a program to identify and analyze structural motifs in proteins. Protein Sci. 5, 212–220.
Jmol: an open-source Java viewer for chemical structures in 3D. http://www.jmol.org/
Stroud, R.M., S. Choe, J. Holton, H.R. Kaback, et al. (2009) 2007 annual progress report synopsis of the Center for Structures of Membrane Proteins. J Struct Funct Genomics. 10, 193–208.
Elsliger, M.A., A.M. Deacon, A. Godzik, S.A. Lesley, et al. (2010) The JCSG high-throughput structural biology pipeline. Acta Crystallogr Sect F Struct Biol Cryst Commun. 66, 1137–1142.
Vroling, B., M. Sanders, C. Baakman, A. Borrmann, et al. (2011) GPCRDB: information system for G protein-coupled receptors. Nucleic Acids Res. 39, D309–319.
Xiao, R., S. Anderson, J. Aramini, R. Belote, et al. (2010) The high-throughput protein sample production platform of the Northeast Structural Genomics Consortium. J Struct Biol. 172, 21–33.
Bonanno, J.B., S.C. Almo, A. Bresnick, M.R. Chance, et al. (2005) New York-Structural GenomiX Research Consortium (NYSGXRC): a large scale center for the protein structure initiative. J Struct Funct Genomics. 6, 225–232.
Nierman, W.C., T.V. Feldblyum, M.T. Laub, I.T. Paulsen, et al. (2001) Complete genome sequence of Caulobacter crescentus. Proc Natl Acad Sci U S A. 98, 4136–4141.
Aldridge, P., R. Paul, P. Goymer, P. Rainey, et al. (2003) Role of the GGDEF regulator PleD in polar development of Caulobacter crescentus. Mol Microbiol. 47, 1695–1708.
Jenal, U. and J. Malone. (2006) Mechanisms of cyclic-di-GMP signaling in bacteria. Annu Rev Genet. 40, 385–407.
Wu, C.H., R. Apweiler, A. Bairoch, D.A. Natale, et al. (2006) The Universal Protein Resource (UniProt): an expanding universe of protein information. Nucleic Acids Res. 34, D187–191.
Hunter, S., R. Apweiler, T.K. Attwood, A. Bairoch, et al. (2009) InterPro: the integrative protein signature database. Nucleic Acids Res. 37, D211–215.
Chan, C., R. Paul, D. Samoray, N.C. Amiot, et al. (2004) Structural basis of activity and allosteric control of diguanylate cyclase. Proc Natl Acad Sci U S A. 101, 17084–17089.
Wassmann, P., C. Chan, R. Paul, A. Beck, et al. (2007) Structure of BeF3- -modified response regulator PleD: implications for diguanylate cyclase activation, catalysis, and feedback inhibition. Structure. 15, 915–927.
De, N., M. Pirruccello, P.V. Krasteva, N. Bae, et al. (2008) Phosphorylation-independent regulation of the diguanylate cyclase WspR. PLoS Biol. 6, e67.
Sigrist, C.J., L. Cerutti, E. de Castro, P.S. Langendijk-Genevaux, et al. (2010) PROSITE, a protein domain database for functional characterization and annotation. Nucleic Acids Res. 38, D161–166.
Dunbrack, R.L., Jr. (2006) Sequence comparison and protein structure prediction. Curr Opin Struct Biol. 16, 374–384.
Waterhouse, A.M., J.B. Procter, D.M. Martin, M. Clamp, et al. (2009) Jalview Version 2 – a multiple sequence alignment editor and analysis workbench. Bioinformatics. 25, 1189–1191.
Rost, B. (1999) Twilight zone of protein sequence alignments. Protein Eng. 12, 85–94.
Krissinel, E. and K. Henrick. (2007) Inference of macromolecular assemblies from crystalline state. J Mol Biol. 372, 774–797.
Paul, R., S. Abel, P. Wassmann, A. Beck, et al. (2007) Activation of the diguanylate cyclase PleD by phosphorylation-mediated dimerization. J Biol Chem. 282, 29170–29177.
Paul, R., S. Abel, P. Wassmann, A. Beck, et al. (2007) Activation of the diguanylate cyclase PleD by phosphorylation-mediated dimerization. J Biol Chem. 282, 29170–29177.
Benkert, P., M. Biasini, and T. Schwede. (2011) Toward the estimation of the absolute quality of individual protein structure models. Bioinformatics. 27, 343–350.
Ramachandran, G.N., C. Ramakrishnan, and V. Sasisekharan. (1963) Stereochemistry of polypeptide chain configurations. J Mol Biol. 7, 95–99.
Briggs, R., L. Dworkin, J. Briggs, E. Dessypris, et al. (1994) Interferon alpha selectively affects expression of the human myeloid cell nuclear differentiation antigen in late stage cells in the monocytic but not the granulocytic lineage. J Cell Biochem. 54, 198–206.
Briggs, R.C., J.A. Briggs, J. Ozer, L. Sealy, et al. (1994) The human myeloid cell nuclear differentiation antigen gene is one of at least two related interferon-inducible genes located on chromosome 1q that are expressed specifically in hematopoietic cells. Blood. 83, 2153–2162.
Dawson, M.J., J.A. Trapani, R.C. Briggs, J.K. Nicholl, et al. (1995) The closely linked genes encoding the myeloid nuclear differentiation antigen (MNDA) and IFI16 exhibit contrasting haemopoietic expression. Immunogenetics. 41, 40–43.
Pruitt, K.D., T. Tatusova, W. Klimke, and D.R. Maglott. (2009) NCBI Reference Sequences: current status, policy and new initiatives. Nucleic Acids Res. 37, D32–36.
Kersey, P.J., J. Duarte, A. Williams, Y. Karavidopoulou, et al. (2004) The International Protein Index: an integrated database for proteomics experiments. Proteomics. 4, 1985–1988.
Benson, D.A., I. Karsch-Mizrachi, D.J. Lipman, J. Ostell, et al. (2011) GenBank. Nucleic Acids Res. 39, D32–37.
Baxevanis, A.D. (2008) Searching NCBI databases using Entrez. Curr Protoc Bioinformatics. Chapter 1, Unit 1 3.
Chen, L., R. Oughtred, H.M. Berman, and J. Westbrook. (2004) TargetDB: a target registration database for structural genomics projects. Bioinformatics. 20, 2860–2862.
Saito, K., M. Inoue, S. Koshiba, T. Kigawa, et al. (2006) DOI:10.2210/pdb2dbg/pdb.
Fairbrother, W.J., N.C. Gordon, E.W. Humke, K.M. O’Rourke, et al. (2001) The PYRIN domain: a member of the death domain-fold superfamily. Protein Sci. 10, 1911–1918.
Koh, I.Y., V.A. Eyrich, M.A. Marti-Renom, D. Przybylski, et al. (2003) EVA: Evaluation of protein structure prediction servers. Nucleic Acids Res. 31, 3311–3315.
Kopp, J., L. Bordoli, J.N.D. Battey, F. Kiefer, et al. (2007) Assessment of CASP7 Predictions for Template-Based Modeling Targets. Proteins: Structure, Function, and Bioinformatics. 69, 38–56.
Liao, J.C.C., R. Lam, M. Ravichandran, J. Ma, et al. (2007) DOI:10.2210/pdb2oq0/pdb.
Schwede, T., J. Kopp, N. Guex, and M.C. Peitsch. (2003) SWISS-MODEL: An automated protein homology-modeling server. Nucleic Acids Res. 31, 3381–3385.
Caly, D.L., P.W. O’Toole, and S.A. Moore. (2010) The 2.2-Å structure of the HP0958 protein from Helicobacter pylori reveals a kinked anti-parallel coiled-coil hairpin domain and a highly conserved ZN-ribbon domain. J Mol Biol. 403, 405–419.
Radivojac, P., L.M. Iakoucheva, C.J. Oldfield, Z. Obradovic, et al. (2007) Intrinsic disorder and functional proteomics. Biophys J. 92, 1439–1456.
Bordoli, L., F. Kiefer, K. Arnold, P. Benkert, et al. (2009) Protein structure homology modeling using SWISS-MODEL workspace. Nat Protoc. 4, 1–13.
Acknowledgments
The authors thank Konstantin Arnold for his dedicated support of the SWISS-MODEL service, Jürgen Haas for his commitment to new developments in PMP, and all members of the group for fruitful discussions.
Funding: The development and operation of SWISS-MODEL was supported by the SIB Swiss Institute of Bioinformatics; The PMP of the Nature PSI Structural Biology Knowledgebase was supported by the National Institutes of Health NIH as a subgrant with Rutgers University, under Prime Agreement Award Numbers: 3U54GM074958-04S2 and 1U01 GM093324-01.
Author information
Authors and Affiliations
Corresponding author
Editor information
Editors and Affiliations
Rights and permissions
Copyright information
© 2011 Springer Science+Business Media,LLC
About this protocol
Cite this protocol
Bordoli, L., Schwede, T. (2011). Automated Protein Structure Modeling with SWISS-MODEL Workspace and the Protein Model Portal. In: Orry, A., Abagyan, R. (eds) Homology Modeling. Methods in Molecular Biology, vol 857. Humana Press. https://doi.org/10.1007/978-1-61779-588-6_5
Download citation
DOI: https://doi.org/10.1007/978-1-61779-588-6_5
Published:
Publisher Name: Humana Press
Print ISBN: 978-1-61779-587-9
Online ISBN: 978-1-61779-588-6
eBook Packages: Springer Protocols