Abstract
Genome sequencing projects have resulted in a rapid increase in the number of known protein sequences. In contrast, only about one-hundredth of these sequences have been characterized at atomic resolution using experimental structure determination methods. Computational protein structure modeling techniques have the potential to bridge this sequence–structure gap. In this chapter, we present an example that illustrates the use of MODELLER to construct a comparative model for a protein with unknown structure. Automation of a similar protocol has resulted in models of useful accuracy for domains in more than half of all known protein sequences.
Access this chapter
Tax calculation will be finalised at checkout
Purchases are for personal use only
Similar content being viewed by others
References
Baker D, Sali A (2001) Protein structure prediction and structural genomics. Science 294(5540):93–96
Schwede T, Sali A, Honig B et al (2009) Outcome of a workshop on applications of protein models in biomedical research. Structure 17(2):151–159
Zhang Y (2008) Progress and challenges in protein structure prediction. Curr Opin Struct Biol 18(3):342–348
Marti-Renom MA, Stuart AC, Fiser A et al (2000) Comparative protein structure modeling of genes and genomes. Annu Rev Biophys Biomol Struct 29:291–325
Eswar N, Sali A (2009) Protein structure modeling. In: Sussman JL, Spadon P (eds) From molecules to medicine, structure of biological macromolecules and its relevance in combating new diseases and bioterrorism, NATO science for peace and security series: a—chemistry and biology. Springer, Dordrecht, The Netherlands, pp 139–151
Ginalski K (2006) Comparative modeling for protein structure prediction. Curr Opin Struct Biol 16(2):172–177
Das R, Baker D (2008) Macromolecular modeling with rosetta. Annu Rev Biochem 77:363–382
Zhang Y, Skolnick J (2004) Automated structure prediction of weakly homologous proteins on a genomic scale. Proc Natl Acad Sci USA 101(20):7594–7599
Simons KT, Bonneau R, Ruczinski I, et al (1999) Ab initio protein structure prediction of CASP III targets using ROSETTA. Proteins (Suppl 3):171–176
Pieper U, Webb BM, Barkan DT et al (2011) ModBase, a database of annotated comparative protein structure models, and associated resources. Nucleic Acids Res 39:465–474
Fiser A, Do RKG, Sali A (2000) Modeling of loops in protein structures. Protein Sci 9(9):1753–1773
Sali A, Blundell TL (1993) Comparative protein modelling by satisfaction of spatial restraints. J Mol Biol 234(3):779–815
Marti-Renom MA, Madhusudhan MS, Sali A (2004) Alignment of protein sequences by their profiles. Protein Sci 13(4):1071–1087
Madhusudhan MS, Marti-Renom MA, Sanchez R et al (2006) Variable gap penalty for protein sequence-structure alignment. Protein Eng Des Sel 19(3):129–133
Madhusudhan MS, Webb BM, Marti-Renom MA et al (2009) Alignment of multiple protein structures based on sequence and structure features. Protein Eng Des Sel 22:569–574
Brooks BR, Brooks CL 3rd, Mackerell AD Jr et al (2009) CHARMM: the biomolecular simulation program. J Comput Chem 30(10):1545–1614
Sali A, Overington JP (1994) Derivation of rules for comparative protein modeling from a database of protein structure alignments. Protein Sci 3(9):1582–1596
Shen MY, Sali A (2006) Statistical potential for assessment and prediction of protein structures. Protein Sci 15(11):2507–2524
Wu G, Fiser A, ter Kuile B et al (1999) Convergent evolution of Trichomonas vaginalis lactate dehydrogenase from malate dehydrogenase. Proc Natl Acad Sci USA 96(11):6285–6290
Berman HM, Westbrook J, Feng Z et al (2000) The protein data bank. Nucleic Acids Res 28(1):235–242
Smith TF, Waterman MS (1981) Identification of common molecular subsequences. J Mol Biol 147(1):195–197
Needleman SB, Wunsch CD (1970) A general method applicable to the search for similarities in the amino acid sequence of two proteins. J Mol Biol 48(3):443–453
John B, Sali A (2003) Comparative protein structure modeling by iterative alignment, model building and model assessment. Nucleic Acids Res 31(14):3982–3992
Melo F, Sanchez R, Sali A (2002) Statistical potentials for fold assessment. Protein Sci 11(2):430–448
Eramian D, Eswar N, Shen M et al (2008) How well can the accuracy of comparative protein structure models be predicted? Protein Sci 17(11):1881–1893
Vajda S, Kozakov D (2009) Convergence and combination of methods in protein–protein docking. Curr Opin Struct Biol 19(2):164–170
Lensink MF, Wodak SJ (2010) Docking and scoring protein interactions: CAPRI 2009. Proteins 78(15):3073–3084
Alber F, Forster F, Korkin D et al (2008) Integrating diverse data for structure determination of macromolecular assemblies. Annu Rev Biochem 77:443–477
Russel D, Lasker K, Webb B et al (2012) Putting the pieces together: integrative structure determination of macromolecular assemblies. PLoS Biol 10(1):e1001244
Robinson C, Sali A, Baumeister W (2007) The molecular sociology of the cell. Nature 450(7172):973–982
Ward A, Sali A, Wilson I (2013) Structural biology unleashed. Science 339:913–915
Lasker K, Sali A, Wolfson HJ (2010) Determining macromolecular assembly structures by molecular docking and fitting into an electron density map. Proteins Struct Funct Bioinform 78:3205–3211
Tjioe E, Lasker K, Webb B et al (2011) MultiFit: a web server for fitting multiple protein structures into their electron microscopy density map. Nucleic Acids Res 39:167–170
Schneidman-Duhovny D, Hammel M, Sali A (2011) Macromolecular docking restrained by a small angle X-ray scattering profile. J Struct Biol 3:461–471
Rost B (1999) Twilight zone of protein sequence alignments. Protein Eng 12(2):85–94
May AC (2004) Percent sequence identity; the need to be explicit. Structure 12(5):737–738
Altschul SF, Madden TL, Schaffer AA et al (1997) Gapped BLAST and PSI-BLAST: a new generation of protein database search programs. Nucleic Acids Res 25(17):3389–3402
Pearson WR (1998) Empirical statistical estimates for sequence similarity searches. J Mol Biol 276(1):71–84
Henikoff S, Henikoff JG (1992) Amino acid substitution matrices from protein blocks. Proc Natl Acad Sci USA 89(22):10915–10919
Zhou H, Zhou Y (2005) Fold recognition by combining sequence profiles derived from evolution and from depth-dependent structural alignment of fragments. Proteins 58(2):321–328
McGuffin LJ, Jones DT (2003) Improvement of the GenTHREADER method for genomic fold recognition. Bioinformatics 19(7):874–881
Karchin R, Cline M, Mandel-Gutfreund Y et al (2003) Hidden Markov models that use predicted local structure for fold recognition: alphabets of backbone geometry. Proteins 51(4):504–514
Shi J, Blundell TL, Mizuguchi K (2001) FUGUE: sequence-structure homology recognition using environment-specific substitution tables and structure-dependent gap penalties. J Mol Biol 310(1):243–257
Dunbrack RL Jr (2006) Sequence comparison and protein structure prediction. Curr Opin Struct Biol 16(3):374–384
Xiang Z (2006) Advances in homology protein structure modeling. Curr Protein Pept Sci 7(3):217–227
Eramian D, Shen M, Devos D et al (2006) A composite score for predicting errors in protein structure models. Protein Sci 15(7):1653–1666
Jacobson MP, Pincus DL, Rapp CS et al (2004) A hierarchical approach to all-atom protein loop prediction. Proteins 55(2):351–367
Zhao S, Zhu K, Li J et al (2011) Progress in super long loop prediction. Proteins 79(10):2920–2935
Fernandez-Fuentes N, Oliva B, Fiser A (2006) A supersecondary structure library and search algorithm for modeling loops in protein structures. Nucleic Acids Res 34(7):2085–2097
van Vlijmen HW, Karplus M (1997) PDB-based protein loop prediction: parameters for selection and methods for optimization. J Mol Biol 267(4):975–1001
Coutsias EA, Seok C, Jacobson MP et al (2004) A kinematic view of loop closure. J Comput Chem 25(4):510–528
Sanchez R, Sali A (1997) Evaluation of comparative protein structure modeling by MODELLER-3. Proteins (Suppl 1):50–58
Srinivasan N, Blundell TL (1993) An evaluation of the performance of an automated procedure for comparative modelling of protein tertiary structure. Protein Eng 6(5):501–512
Sanchez R, Sali A (1998) Large-scale protein structure modeling of the Saccharomyces cerevisiae genome. Proc Natl Acad Sci USA 95(23):13597–13602
Chothia C, Lesk AM (1986) The relation between the divergence of sequence and structure in proteins. EMBO J 5(4):823–826
Acknowledgments
We are grateful to all members of our research group. We also acknowledge support from National Institutes of Health (U54 GM094625) as well as computing hardware support from Ron Conway, Mike Homer, Hewlett-Packard, NetApp, IBM, and Intel.
Author information
Authors and Affiliations
Editor information
Editors and Affiliations
Rights and permissions
Copyright information
© 2014 Springer Science+Business Media New York
About this protocol
Cite this protocol
Webb, B., Sali, A. (2014). Protein Structure Modeling with MODELLER . In: Kihara, D. (eds) Protein Structure Prediction. Methods in Molecular Biology, vol 1137. Humana Press, New York, NY. https://doi.org/10.1007/978-1-4939-0366-5_1
Download citation
DOI: https://doi.org/10.1007/978-1-4939-0366-5_1
Published:
Publisher Name: Humana Press, New York, NY
Print ISBN: 978-1-4939-0365-8
Online ISBN: 978-1-4939-0366-5
eBook Packages: Springer Protocols