Template-Based Protein Structure Modeling

  • Andras Fiser
Part of the Methods in Molecular Biology book series (MIMB, volume 673)


Functional characterization of a protein is often facilitated by its 3D structure. However, the fraction of experimentally known 3D models is currently less than 1% due to the inherently time-consuming and complicated nature of structure determination techniques. Computational approaches are employed to bridge the gap between the number of known sequences and that of 3D models. Template-based protein structure modeling techniques rely on the study of principles that dictate the 3D structure of natural proteins from the theory of evolution viewpoint. Strategies for template-based structure modeling will be discussed with a focus on comparative modeling, by reviewing techniques available for all the major steps involved in the comparative modeling pipeline.

Key words

Homology modeling Comparative protein structure modeling Template-based modeling Loop modeling Side chain modeling Sequence-to-structure alignment 



This review is partially based on our previous publications (1, 144).


  1. 1.
    Fiser, A. (2004) Protein structure modeling in the proteomics era. Expert Rev Proteomics, 1, 97–110.PubMedCrossRefGoogle Scholar
  2. 2.
    Marti-Renom, M.A., Stuart, A.C., Fiser, A., Sanchez, R., Melo, F., and Sali, A. (2000) Comparative protein structure modeling of genes and genomes. Annu Rev Biophys Biomol Struct, 29, 291.PubMedCrossRefGoogle Scholar
  3. 3.
    Chothia, C. and Lesk, A.M. (1986) The relation between the divergence of sequence and structure in proteins. EMBO J, 5, 823.PubMedGoogle Scholar
  4. 4.
    Lesk, A.M. and Chothia, C. (1980) How different amino acid sequences determine similar protein structures: the structure and evolutionary dynamics of the globins. J Mol Biol, 136, 225.PubMedCrossRefGoogle Scholar
  5. 5.
    Andreeva, A., Howorth, D., Chandonia, J.M., Brenner, S.E., Hubbard, T.J., Chothia, C., and Murzin, A.G. (2008) Data growth and its impact on the SCOP database: new developments. Nucleic Acids Res, 36, D419–D425.PubMedCrossRefGoogle Scholar
  6. 6.
    Chothia, C., Gough, J., Vogel, C., and Teichmann, S.A. (2003) Evolution of the protein repertoire. Science, 300, 1701.PubMedCrossRefGoogle Scholar
  7. 7.
    Greene, L.H., Lewis, T.E., Addou, S., Cuff, A., Dallman, T., Dibley, M., Redfern, O., Pearl, F., Nambudiry, R., Reid, A., et al. (2007) The CATH domain structure database: new protocols and classification levels give a more comprehensive resource for exploring evolution. Nucleic Acids Res, 35, D291–D297.PubMedCrossRefGoogle Scholar
  8. 8.
    Pieper, U., Eswar, N., Davis, F.P., Braberg, H., Madhusudhan, M.S., Rossi, A., Marti-Renom, M., Karchin, R., Webb, B.M., Eramian, D., et al. (2006) MODBASE: a database of annotated comparative protein structure models and associated resources. Nucleic Acids Res, 34, D291–D295.PubMedCrossRefGoogle Scholar
  9. 9.
    Berman, H., Henrick, K., Nakamura, H., and Markley, J.L. (2007) The worldwide Protein Data Bank (wwPDB): ensuring a single, uniform archive of PDB data. Nucleic Acids Res, 35, D301–D303.PubMedCrossRefGoogle Scholar
  10. 10.
    Zhang, Y. (2007) Template-based modeling and free modeling by I-TASSER in CASP7. Proteins, 69 Suppl 8, 108–117.PubMedCrossRefGoogle Scholar
  11. 11.
    Das, R., Qian, B., Raman, S., Vernon, R., Thompson, J., Bradley, P., Khare, S., Tyka, M.D., Bhat, D., Chivian, D., et al. (2007) Structure prediction for CASP7 targets using extensive all-atom refinement with Rosetta@home. Proteins, 69 Suppl 8, 118–128.PubMedCrossRefGoogle Scholar
  12. 12.
    Battey, J.N., Kopp, J., Bordoli, L., Read, R.J., Clarke, N.D., and Schwede, T. (2007) Automated server predictions in CASP7. Proteins, 69 Suppl 8, 68–82.PubMedCrossRefGoogle Scholar
  13. 13.
    Fernandez-Fuentes, N., Madrid-Aliste, C.J., Rai, B.K., Fajardo, J.E., and Fiser, A. (2007) M4T: a comparative protein structure modeling server. Nucleic Acids Res, 35, W363–W368.PubMedCrossRefGoogle Scholar
  14. 14.
    Rai, B.K., Madrid-Aliste, C.J., Fajardo, J.E., and Fiser, A. (2006) MMM: a sequence-to-structure alignment protocol. Bioinformatics, 22, 2691–2692.PubMedCrossRefGoogle Scholar
  15. 15.
    Kopp, J., Bordoli, L., Battey, J.N., Kiefer, F., and Schwede, T. (2007) Assessment of CASP7 predictions for template-based modeling targets. Proteins, 69 Suppl 8, 38–56.PubMedCrossRefGoogle Scholar
  16. 16.
    Fiser, A. and Sali, A. (2003) Modeller: generation and refinement of homology-based protein structure models. Methods Enzymol, 374, 461.PubMedCrossRefGoogle Scholar
  17. 17.
    Fernandez-Fuentes, N., Rai, B.K., Madrid-Aliste, C.J., Fajardo, J.E., and Fiser, A. (2007) Comparative protein structure modeling by combining multiple templates and optimizing sequence-to-structure alignments. Bioinformatics, 23, 2558–2565.PubMedCrossRefGoogle Scholar
  18. 18.
    Contreras-Moreira, B., Fitzjohn, P.W., Offman, M., Smith, G.R., and Bates, P.A. (2003) Novel use of a genetic algorithm for protein structure prediction: searching template and sequence alignment space. Proteins, 53 Suppl 6, 424.Google Scholar
  19. 19.
    Schaffer, A.A., Aravind, L., Madden, T.L., Shavirin, S., Spouge, J.L., Wolf, Y.I., Koonin, E.V., and Altschul, S.F. (2001) Improving the accuracy of PSI-BLAST protein database searches with composition-based statistics and other refinements. Nucleic Acids Res, 29, 2994.PubMedCrossRefGoogle Scholar
  20. 20.
    Apostolico, A. and Giancarlo, R. (1998) Sequence alignment in molecular biology. J Comput Biol, 5, 173.PubMedCrossRefGoogle Scholar
  21. 21.
    Pearson, W.R. (2000) Flexible sequence similarity searching with the FASTA3 program package. Methods Mol Biol, 132, 185.PubMedGoogle Scholar
  22. 22.
    Sauder, J.M., Arthur, J.W., and Dunbrack, R.L., Jr. (2000) Large-scale comparison of protein sequence alignment algorithms with structure alignments. Proteins, 40, 6.PubMedCrossRefGoogle Scholar
  23. 23.
    Brenner, S.E., Chothia, C., and Hubbard, T.J. (1998) Assessing sequence comparison methods with reliable structurally identified distant evolutionary relationships. Proc Natl Acad Sci U S A, 95, 6073.PubMedCrossRefGoogle Scholar
  24. 24.
    Rychlewski, L., Jaroszewski, L., Li, W., and Godzik, A. (2000) Comparison of sequence profiles. Strategies for structural predictions using sequence information. Protein Sci, 9, 232.PubMedCrossRefGoogle Scholar
  25. 25.
    Krogh, A., Brown, M., Mian, I.S., Sjolander, K., and Haussler, D. (1994) Hidden Markov models in computational biology. Applications to protein modeling. J Mol Biol, 235, 1501.PubMedCrossRefGoogle Scholar
  26. 26.
    Henikoff, J.G., Pietrokovski, S., McCallum, C.M., and Henikoff, S. (2000) Blocks-based methods for detecting protein homology. Electrophoresis, 21, 1700.PubMedCrossRefGoogle Scholar
  27. 27.
    Altschul, S.F., Madden, T.L., Schaffer, A.A., Zhang, J., Zhang, Z., Miller, W., and Lipman, D.J. (1997) Gapped BLAST and PSI-BLAST: a new generation of protein database search programs. Nucleic Acids Res, 25, 3389.PubMedCrossRefGoogle Scholar
  28. 28.
    Marti-Renom, M.A., Madhusudhan, M.S., and Sali, A. (2004) Alignment of protein sequences by their profiles. Protein Sci, 13, 1071.PubMedCrossRefGoogle Scholar
  29. 29.
    Notredame, C. (2007) Recent evolutions of multiple sequence alignment algorithms. PLoS Comput Biol, 3, e123.PubMedCrossRefGoogle Scholar
  30. 30.
    Edgar, R.C. and Batzoglou, S. (2006) Multiple sequence alignment. Curr Opin Struct Biol, 16, 368–373.PubMedCrossRefGoogle Scholar
  31. 31.
    Edgar, R.C. and Sjolander, K. (2004) COACH: profile–profile alignment of protein families using hidden Markov models. Bioinformatics, 20, 1309.PubMedCrossRefGoogle Scholar
  32. 32.
    Jaroszewski, L., Rychlewski, L., Zhang, B., and Godzik, A. (1998) Fold prediction by a hierarchy of sequence, threading, and modeling methods. Protein Sci, 7, 1431.PubMedCrossRefGoogle Scholar
  33. 33.
    Jaroszewski, L., Rychlewski, L., Li, Z., Li, W., and Godzik, A. (2005) FFAS03: a server for profile–profile sequence alignments. Nucleic Acids Res, 33, W284–W288.PubMedCrossRefGoogle Scholar
  34. 34.
    Karplus, K., Barrett, C., and Hughey, R. (1998) Hidden Markov models for detecting remote protein homologies. Bioinformatics, 14, 846.PubMedCrossRefGoogle Scholar
  35. 35.
    Karchin, R., Cline, M., Mandel-Gutfreund, Y., and Karplus, K. (2003) Hidden Markov models that use predicted local structure for fold recognition: alphabets of backbone geometry. Proteins, 51, 504.PubMedCrossRefGoogle Scholar
  36. 36.
    Karplus, K., Katzman, S., Shackleford, G., Koeva, M., Draper, J., Barnes, B., Soriano, M., and Hughey, R. (2005) SAM-T04: what is new in protein-structure prediction for CASP6. Proteins, 61 Suppl 7, 135–142.PubMedCrossRefGoogle Scholar
  37. 37.
    Edgar, R.C. and Sjolander, K. (2003) SATCHMO: sequence alignment and tree construction using hidden Markov models. Bioinformatics, 19, 1404.PubMedCrossRefGoogle Scholar
  38. 38.
    John, B. and Sali, A. (2004) Detection of homologous proteins by an intermediate sequence search. Protein Sci, 13, 54.PubMedCrossRefGoogle Scholar
  39. 39.
    Moretti, S., Armougom, F., Wallace, I.M., Higgins, D.G., Jongeneel, C.V., and Notredame, C. (2007) The M-Coffee web server: a meta-method for computing multiple sequence alignments by combining alternative alignment methods. Nucleic Acids Res, 35, W645–W648.PubMedCrossRefGoogle Scholar
  40. 40.
    Pei, J., Kim, B.H., and Grishin, N.V. (2008) PROMALS3D: a tool for multiple protein sequence and structure alignments. Nucleic Acids Res, 36, 2295–2300.PubMedCrossRefGoogle Scholar
  41. 41.
    Pei, J. and Grishin, N.V. (2007) PROMALS: towards accurate multiple sequence alignments of distantly related proteins. Bioinformatics, 23, 802–808.PubMedCrossRefGoogle Scholar
  42. 42.
    Do, C.B., Mahabhashyam, M.S., Brudno, M., and Batzoglou, S. (2005) ProbCons: probabilistic consistency-based multiple sequence alignment. Genome Res, 15, 330.PubMedCrossRefGoogle Scholar
  43. 43.
    Jones, D.T. (1999) GenTHREADER: an efficient and reliable protein fold recognition method for genomic sequences. J Mol Biol, 287, 797.PubMedCrossRefGoogle Scholar
  44. 44.
    Finkelstein, A.V. and Reva, B.A. (1991) A search for the most stable folds of protein chains. Nature, 351, 497.PubMedCrossRefGoogle Scholar
  45. 45.
    Bowie, J.U., Luthy, R., and Eisenberg, D. (1991) A method to identify protein sequences that fold into a known three-dimensional structure. Science, 253, 164.PubMedCrossRefGoogle Scholar
  46. 46.
    Sippl, M.J. (1995) Knowledge-based potentials for proteins. Curr Opin Struct Biol, 5, 229.PubMedCrossRefGoogle Scholar
  47. 47.
    Shi, J., Blundell, T.L., and Mizuguchi, K. (2001) FUGUE: sequence–structure homology recognition using environment-specific substitution tables and structure-dependent gap penalties. J Mol Biol, 310, 243.PubMedCrossRefGoogle Scholar
  48. 48.
    Felsenstein, J. (1981) Evolutionary trees from DNA sequences: a maximum likelihood approach. J Mol Evol, 17, 368.PubMedCrossRefGoogle Scholar
  49. 49.
    Venclovas, C. and Margelevicius, M. (2005) Comparative modeling in CASP6 using consensus approach to template selection, sequence–structure alignment, and structure assessment. Proteins, 61, 99–105.PubMedCrossRefGoogle Scholar
  50. 50.
    Sanchez, R. and Sali, A. (1997) Evaluation of comparative protein structure modeling by MODELLER-3. Proteins, 1 Suppl, 50.PubMedCrossRefGoogle Scholar
  51. 51.
    Eisenberg, D., Luthy, R., and Bowie, J.U. (1997) VERIFY3D: assessment of protein models with three-dimensional profiles. Methods Enzymol, 277, 396.PubMedCrossRefGoogle Scholar
  52. 52.
    Wu, G., McArthur, A.G., Fiser, A., Sali, A., Sogin, M.L., and Mllerm, M. (2000) Core histones of the amitochondriate protist, Giardia lamblia. Mol Biol Evol, 17, 1156.PubMedCrossRefGoogle Scholar
  53. 53.
    Jennings, A.J., Edge, C.M., and Sternberg, M.J. (2001) An approach to improving multiple alignments of protein sequences using predicted secondary structure. Protein Eng, 14, 227.PubMedCrossRefGoogle Scholar
  54. 54.
    Blake, J.D. and Cohen, F.E. (2001) Pairwise sequence alignment below the twilight zone. J Mol Biol, 307, 721.PubMedCrossRefGoogle Scholar
  55. 55.
    Petrey, D., Xiang, Z., Tang, C.L., Xie, L., Gimpelev, M., Mitros, T., Soto, C.S., Goldsmith-Fischman, S., Kernytsky, A., Schlessinger, A., et al. (2003) Using multiple structure alignments, fast model building, and energetic analysis in fold recognition and homology modeling. Proteins, 53 Suppl 6, 430.Google Scholar
  56. 56.
    Al Lazikani, B., Sheinerman, F.B., and Honig, B. (2001) Combining multiple structure and sequence alignments to improve sequence detection and alignment: application to the SH2 domains of Janus kinases. Proc Natl Acad Sci U S A, 98, 14796.PubMedCrossRefGoogle Scholar
  57. 57.
    Reddy, B.V., Li, W.W., Shindyalov, I.N., and Bourne, P.E. (2001) Conserved key amino acid positions (CKAAPs) derived from the analysis of common substructures in proteins. Proteins, 42, 148.PubMedCrossRefGoogle Scholar
  58. 58.
    Jaroszewski, L., Rychlewski, L., and Godzik, A. (2000) Improving the quality of twilight-zone alignments. Protein Sci, 9, 1487.PubMedCrossRefGoogle Scholar
  59. 59.
    Rai, B.K. and Fiser, A. (2006) Multiple mapping method: a novel approach to the sequence-to-structure alignment problem in comparative protein structure modeling. Proteins, 63, 644–661.PubMedCrossRefGoogle Scholar
  60. 60.
    Henikoff, S. and Henikoff, J.G. (1992) Amino acid substitution matrices from protein blocks. Proc Natl Acad Sci U S A, 89, 10915–10919.PubMedCrossRefGoogle Scholar
  61. 61.
    Luthy, R., McLachlan, A.D., and Eisenberg, D. (1991) Secondary structure-based profiles: use of structure-conserving scoring tables in searching protein sequence databases for structural similarities. Proteins, 10, 229–239.PubMedCrossRefGoogle Scholar
  62. 62.
    Rykunov, D. and Fiser, A. (2007) Effects of amino acid composition, finite size of proteins, and sparse statistics on distance-dependent statistical pair potentials. Proteins, 67, 559–568.PubMedCrossRefGoogle Scholar
  63. 63.
    Blundell, T.L., Sibanda, B.L., Sternberg, M.J., and Thornton, J.M. (1987) Knowledge-based prediction of protein structures and the design of novel molecules. Nature, 326, 347.PubMedCrossRefGoogle Scholar
  64. 64.
    Browne, W.J., North, A.C.T., Phillips, D.C., Brew, K., Vanaman, T.C., and Hill, R.C. (1969) A possible three-dimensional structure of bovine lactalbumin based on that of hen’s egg-white lysosyme. J Mol Biol, 42, 65.PubMedCrossRefGoogle Scholar
  65. 65.
    Greer, J. (1990) Comparative modeling methods: application to the family of the mammalian serine proteases. Proteins, 7, 317.PubMedCrossRefGoogle Scholar
  66. 66.
    Topham, C.M., McLeod, A., Eisenmenger, F., Overington, J.P., Johnson, M.S., and Blundell, T.L. (1993) Fragment ranking in modelling of protein structure. Conformationally constrained environmental amino acid substitution tables. J Mol Biol, 229, 194.PubMedCrossRefGoogle Scholar
  67. 67.
    Sutcliffe, M.J., Haneef, I., Carney, D., and Blundell, T.L. (1987) Knowledge based modelling of homologous proteins, part I: three-dimensional frameworks derived from the simultaneous superposition of multiple structures. Protein Eng, 1, 377.PubMedCrossRefGoogle Scholar
  68. 68.
    Srinivasan, N. and Blundell, T.L. (1993) An evaluation of the performance of an automated procedure for comparative modelling of protein tertiary structure. Protein Eng, 6, 501.PubMedCrossRefGoogle Scholar
  69. 69.
    Claessens, M., Van Cutsem, E., Lasters, I., and Wodak, S. (1989) Modelling the polypeptide backbone with ‘spare parts’ from known protein structures. Protein Eng, 2, 335.PubMedCrossRefGoogle Scholar
  70. 70.
    Holm, L. and Sander, C. (1991) Database algorithm for generating protein backbone and side-chain co-ordinates from a C alpha trace application to model building and detection of co-ordinate errors. J Mol Biol, 218, 183.PubMedCrossRefGoogle Scholar
  71. 71.
    Bruccoleri, R.E. and Karplus, M. (1990) Conformational sampling using high-temperature molecular dynamics. Biopolymers, 29, 1847.PubMedCrossRefGoogle Scholar
  72. 72.
    van Gelder, C.W., Leusen, F.J., Leunissen, J.A., and Noordik, J.H. (1994) A molecular dynamics approach for the generation of complete protein structures from limited coordinate data. Proteins, 18, 174.PubMedCrossRefGoogle Scholar
  73. 73.
    Levitt, M. (1992) Accurate modeling of protein conformation by automatic segment matching. J Mol Biol, 226, 507.PubMedCrossRefGoogle Scholar
  74. 74.
    Chinea, G., Padron, G., Hooft, R.W., Sander, C., and Vriend, G. (1995) The use of position-specific rotamers in model building by homology. Proteins, 23, 415.PubMedCrossRefGoogle Scholar
  75. 75.
    Jones, T.A. and Thirup, S. (1986) Using known substructures in protein model building and crystallography. EMBO J, 5, 819.PubMedGoogle Scholar
  76. 76.
    Brooks, C.L., III, Bruccoleri, R.E., Olafson, B.D., States, D.J., Swaminathan, S., and Karplus, M. (1983) CHARMM: a program for macromolecular energy minimization and dynamics calculations. J Comput Chem, 4, 187.CrossRefGoogle Scholar
  77. 77.
    Sali, A. and Blundell, T.L. (1993) Comparative protein modeling by satisfaction of spatial restraints. J Mol Biol, 234, 779–815.PubMedCrossRefGoogle Scholar
  78. 78.
    Braun, W. and Go, N. (1985) Calculation of protein conformations by proton–proton distance constraints. A new efficient algorithm. J Mol Biol, 186, 611.PubMedCrossRefGoogle Scholar
  79. 79.
    Clore, G.M., Brunger, A.T., Karplus, M., and Gronenborn, A.M. (1986) Application of molecular dynamics with interproton distance restraints to three-dimensional protein structure determination. A model study of crambin. J Mol Biol, 191, 523.PubMedCrossRefGoogle Scholar
  80. 80.
    Guenther, B., Onrust, R., Sali, A., O’Donnell, M., and Kuriyan, J. (1997) Crystal structure of the ë-subunit of the clamp-loader complex of E. coli DNA polymerase III. Cell, 91, 335.PubMedCrossRefGoogle Scholar
  81. 81.
    Fiser, A., Filipe, S.R., and Tomasz, A. (2003) Cell wall branches, penicillin resistance and the secrets of the MurM protein. Trends Microbiol, 11, 547.PubMedCrossRefGoogle Scholar
  82. 82.
    John, B. and Sali, A. (2003) Comparative protein structure modeling by iterative alignment, model building and model assessment. Nucleic Acids Res, 31, 3982.PubMedCrossRefGoogle Scholar
  83. 83.
    Chivian, D. and Baker, D. (2006) Homology modeling using parametric alignment ensemble generation with consensus and energy-based model selection. Nucleic Acids Res, 34, e112.PubMedCrossRefGoogle Scholar
  84. 84.
    Kolinski, A. and Bujnicki, J.M. (2005) Generalized protein structure prediction based on combination of fold-recognition with de novo folding and evaluation of models. Proteins, 61 Suppl 7, 84–90.PubMedCrossRefGoogle Scholar
  85. 85.
    Terashi, G., Takeda-Shitaka, M., Kanou, K., Iwadate, M., Takaya, D., Hosoi, A., Ohta, K., and Umeyama, H. (2007) Fams-ace: a combined method to select the best model after remodeling all server models. Proteins, 69 Suppl 8, 98–107.PubMedCrossRefGoogle Scholar
  86. 86.
    Wallner, B., Larsson, P., and Elofsson, A. (2007) protein structure prediction meta server. Nucleic Acids Res, 35, W369–W374.PubMedCrossRefGoogle Scholar
  87. 87.
    Ginalski, K., Elofsson, A., Fischer, D., and Rychlewski, L. (2003) 3D-Jury: a simple approach to improve protein structure predictions. Bioinformatics, 19, 1015–1018.PubMedCrossRefGoogle Scholar
  88. 88.
    Mezei, M. (1998) Chameleon sequences in the PDB. Protein Eng, 11, 411.PubMedCrossRefGoogle Scholar
  89. 89.
    Fernandez-Fuentes, N. and Fiser, A. (2006) Saturating representation of loop conformational fragments in structure databanks. BMC Struct Biol, 6, 15.PubMedCrossRefGoogle Scholar
  90. 90.
    Shenkin, P.S., Yarmush, D.L., Fine, R.M., Wang, H.J., and Levinthal, C. (1987) Predicting antibody hypervariable loop conformation. I. Ensembles of random conformations for ringlike structures. Biopolymers, 26, 2053.PubMedCrossRefGoogle Scholar
  91. 91.
    Moult, J. and James, M.N. (1986) An algorithm for determining the conformation of polypeptide segments in proteins by systematic search. Proteins, 1, 146.PubMedCrossRefGoogle Scholar
  92. 92.
    Bruccoleri, R.E. and Karplus, M. (1987) Prediction of the folding of short polypeptide segments by uniform conformational sampling. Biopolymers, 26, 137.PubMedCrossRefGoogle Scholar
  93. 93.
    Deane, C.M. and Blundell, T.L. (2001) CODA: a combined algorithm for predicting the structurally variable regions of protein models. Protein Sci, 10, 599.PubMedCrossRefGoogle Scholar
  94. 94.
    van Vlijmen, H.W. and Karplus, M. (1997) PDB-based protein loop prediction: parameters for selection and methods for optimization. J Mol Biol, 267, 975.PubMedCrossRefGoogle Scholar
  95. 95.
    de Bakker, P.I., DePristo, M.A., Burke, D.F., and Blundell, T.L. (2003) Ab initio construction of polypeptide fragments: accuracy of loop decoy discrimination by an all-atom statistical potential and the AMBER force field with the Generalized Born solvation model. Proteins, 51, 21.PubMedCrossRefGoogle Scholar
  96. 96.
    Fidelis, K., Stern, P.S., Bacon, D., and Moult, J. (1994) Comparison of systematic search and database methods for constructing segments of protein structure. Protein Eng, 7, 953.PubMedCrossRefGoogle Scholar
  97. 97.
    Du, P., Andrec, M., and Levy, R.M. (2003) Have we seen all structures corresponding to short protein fragments in the Protein Data Bank? An update. Protein Eng, 16, 407.PubMedCrossRefGoogle Scholar
  98. 98.
    Fernandez-Fuentes, N., Oliva, B., and Fiser, A. (2006) A supersecondary structure library and search algorithm for modeling loops in protein structures. Nucleic Acids Res, 34, 2085–2097.PubMedCrossRefGoogle Scholar
  99. 99.
    Michalsky, E., Goede, A., and Preissner, R. (2003) Loops in proteins (LIP) – a comprehensive loop database for homology modelling. Protein Eng, 16, 979.PubMedCrossRefGoogle Scholar
  100. 100.
    Espadaler, J., Fernandez-Fuentes, N., Hermoso, A., Querol, E., Aviles, F.X., Sternberg, M.J., and Oliva, B. (2004) ArchDB: automated protein loop classification as a tool for structural genomics. Nucleic Acids Res, 32 Database issue, D185.PubMedCrossRefGoogle Scholar
  101. 101.
    Peng, H.P. and Yang, A.S. (2007) Modeling protein loops with knowledge-based prediction of sequence–structure alignment. Bioinformatics, 23, 2836–2842.PubMedCrossRefGoogle Scholar
  102. 102.
    Fernandez-Fuentes, N., Zhai, J., and Fiser, A. (2006) ArchPRED: a template based loop structure prediction server. Nucleic Acids Res, 34, W173–W176.PubMedCrossRefGoogle Scholar
  103. 103.
    Oliva, B., Bates, P.A., Querol, E., Aviles, F.X., and Sternberg, M.J. (1997) An automated classification of the structure of protein loops. J Mol Biol, 266, 814.PubMedCrossRefGoogle Scholar
  104. 104.
    Fine, R.M., Wang, H., Shenkin, P.S., Yarmush, D.L., and Levinthal, C. (1986) Predicting antibody hypervariable loop conformations. II: minimization and molecular dynamics studies of MCPC603 from many randomly generated loop conformations. Proteins, 1, 342.PubMedCrossRefGoogle Scholar
  105. 105.
    Ring, C.S. and Cohen, F.E. (1993) Modeling protein structures: construction and their applications. FASEB J, 7, 783.PubMedGoogle Scholar
  106. 106.
    Abagyan, R. and Totrov, M. (1994) Biased probability Monte Carlo conformational searches and electrostatic calculations for peptides and proteins. J Mol Biol, 235, 983.PubMedCrossRefGoogle Scholar
  107. 107.
    Collura, V., Higo, J., and Garnier, J. (1993) Modeling of protein loops by simulated annealing. Protein Sci, 2, 1502.PubMedCrossRefGoogle Scholar
  108. 108.
    Zheng, Q., Rosenfeld, R., Vajda, S., and DeLisi, C. (1993) Determining protein loop conformation using scaling-relaxation techniques. Protein Sci, 2, 1242.PubMedCrossRefGoogle Scholar
  109. 109.
    Koehl, P. and Delarue, M. (1995) A self consistent mean field approach to simultaneous gap closure and side-chain positioning in homology modelling. Nat Struct Biol, 2, 163.PubMedCrossRefGoogle Scholar
  110. 110.
    Samudrala, R. and Moult, J. (1998) A graph-theoretic algorithm for comparative modeling of protein structure. J Mol Biol, 279, 287.PubMedCrossRefGoogle Scholar
  111. 111.
    Fiser, A. and Sali, A. (2003) ModLoop: automated modeling of loops in protein structures. Bioinformatics, 19, 2500.PubMedCrossRefGoogle Scholar
  112. 112.
    Fiser, A., Do, R.K., and Sali, A. (2000) Modeling of loops in protein structures. Protein Sci, 9, 1753.PubMedCrossRefGoogle Scholar
  113. 113.
    Sippl, M.J. (1990) Calculation of conformational ensembles from potentials of mean force. An approach to the knowledge-based prediction of local structures in globular proteins. J Mol Biol, 213, 859.PubMedCrossRefGoogle Scholar
  114. 114.
    Melo, F. and Feytmans, E. (1997) Novel knowledge-based mean force potential at atomic level. J Mol Biol, 267, 207.PubMedCrossRefGoogle Scholar
  115. 115.
    Fiser, A., Feig, M., Brooks, C.L., III, and Sali, A. (2002) Evolution and physics in comparative protein structure modeling. Acc Chem Res, 35, 413.PubMedCrossRefGoogle Scholar
  116. 116.
    Das, B. and Meirovitch, H. (2003) Solvation parameters for predicting the structure of surface loops in proteins: transferability and entropic effects. Proteins, 51, 470.PubMedCrossRefGoogle Scholar
  117. 117.
    Forrest, L.R. and Woolf, T.B. (2003) Discrimination of native loop conformations in membrane proteins: decoy library design and evaluation of effective energy scoring functions. Proteins, 52, 492.PubMedCrossRefGoogle Scholar
  118. 118.
    DePristo, M.A., de Bakker, P.I., Lovell, S.C., and Blundell, T.L. (2003) Ab initio construction of polypeptide fragments: efficient generation of accurate, representative ensembles. Proteins, 51, 41.PubMedCrossRefGoogle Scholar
  119. 119.
    Xiang, Z., Soto, C.S., and Honig, B. (2002) Evaluating conformational free energies: the colony energy and its application to the problem of loop prediction. Proc Natl Acad Sci U S A, 99, 7432–7437.PubMedCrossRefGoogle Scholar
  120. 120.
    Fogolari, F. and Tosatto, S.C. (2005) Application of MM/PBSA colony free energy to loop decoy discrimination: toward correlation between energy and root mean square deviation. Protein Sci, 14, 889–901.PubMedCrossRefGoogle Scholar
  121. 121.
    Soto, C.S., Fasnacht, M., Zhu, J., Forrest, L., and Honig, B. (2007) Loop modeling: sampling, filtering, and scoring. Proteins, 70, 834–843.CrossRefGoogle Scholar
  122. 122.
    Zhang, C., Liu, S., and Zhou, Y. (2004) Accurate and efficient loop selections by the DFIRE-based all-atom statistical potential. Protein Sci, 13, 391–399.PubMedCrossRefGoogle Scholar
  123. 123.
    Soto, C.S., Fasnacht, M., Zhu, J., Forrest, L., and Honig, B. (2008) Loop modeling: Sampling, filtering, and scoring. Proteins, 70, 834–843.PubMedCrossRefGoogle Scholar
  124. 124.
    Rohl, C.A., Strauss, C.E., Chivian, D., and Baker, D. (2004) Modeling structurally variable regions in homologous proteins with rosetta. Proteins, 55, 656–677.PubMedCrossRefGoogle Scholar
  125. 125.
    Jacobson, M.P., Pincus, D.L., Rapp, C.S., Day, T.J., Honig, B., Shaw, D.E., and Friesner, R.A. (2004) A hierarchical approach to all-atom protein loop prediction. Proteins, 55, 351.PubMedCrossRefGoogle Scholar
  126. 126.
    Laskowski, R.A., Moss, D.S., and Thornton, J.M. (1993) Main-chain bond lengths and bond angles in protein structures. J Mol Biol, 231, 1049.PubMedCrossRefGoogle Scholar
  127. 127.
    Hooft, R.W., Vriend, G., Sander, C., and Abola, E.E. (1996) Errors in protein structures. Nature, 381, 272.PubMedCrossRefGoogle Scholar
  128. 128.
    Sippl, M.J. (1993) Recognition of errors in three-dimensional structures of proteins. Proteins, 17, 355.PubMedCrossRefGoogle Scholar
  129. 129.
    Eramian, D., Shen, M.Y., Devos, D., Melo, F., Sali, A., and Marti-Renom, M.A. (2006) A composite score for predicting errors in protein structure models. Protein Sci, 15, 1653–1666.PubMedCrossRefGoogle Scholar
  130. 130.
    Fasnacht, M., Zhu, J., and Honig, B. (2007) Local quality assessment in homology models using statistical potentials and support vector machines. Protein Sci, 16, 1557–1568.PubMedCrossRefGoogle Scholar
  131. 131.
    Wallner, B. and Elofsson, A. (2007) Prediction of global and local model quality in CASP7 using Pcons and ProQ. Proteins, 69 Suppl 8, 184–193.PubMedCrossRefGoogle Scholar
  132. 132.
    Wallner, B. and Elofsson, A. (2005) Pcons5: combining consensus, structural evaluation and fold recognition scores. Bioinformatics, 21, 4248–4254.PubMedCrossRefGoogle Scholar
  133. 133.
    Moult, J. (2005) A decade of CASP: progress, bottlenecks and prognosis in protein structure prediction. Curr Opin Struct Biol, 15, 285–289.PubMedCrossRefGoogle Scholar
  134. 134.
    Eyrich, V.A., Marti-Renom, M.A., Przybylski, D., Madhusudhan, M.S., Fiser, A., Pazos, F., Valencia, A., Sali, A., and Rost, B. (2001) EVA: continuous automatic evaluation of protein structure prediction servers. Bioinformatics, 17, 1242.PubMedCrossRefGoogle Scholar
  135. 135.
    Bujnicki, J.M., Elofsson, A., Fischer, D., and Rychlewski, L. (2001) LiveBench-1: continuous benchmarking of protein structure prediction servers. Protein Sci, 10, 352.PubMedCrossRefGoogle Scholar
  136. 136.
    Marti-Renom, M.A., Madhusudhan, M.S., Fiser, A., Rost, B., and Sali, A. (2002) Reliability of assessment of protein structure prediction methods. Structure (Camb.), 10, 435.CrossRefGoogle Scholar
  137. 137.
    Wallner, B. and Elofsson, A. (2005) All are not equal: a benchmark of different homology modeling programs. Protein Sci, 14, 1315–1327.PubMedCrossRefGoogle Scholar
  138. 138.
    Dalton, J.A. and Jackson, R.M. (2007) An evaluation of automated homology modelling methods at low target template sequence similarity. Bioinformatics, 23, 1901–1908.PubMedCrossRefGoogle Scholar
  139. 139.
    Baker, D. and Sali, A. (2001) Protein structure prediction and structural genomics. Science, 294, 93–96.PubMedCrossRefGoogle Scholar
  140. 140.
    Sanchez, R. and Sali, A. (1998) Large-scale protein structure modeling of the Saccharomyces cerevisiae genome. Proc Natl Acad Sci U S A, 95, 13597.PubMedCrossRefGoogle Scholar
  141. 141.
    Ohlendorf, D.H. (1994) Accuracy of refined protein structures. Comparison of four independently refined models of human interleukin 1 beta. Acta Crystallogr D Biol Crystallogr, D50, 808.CrossRefGoogle Scholar
  142. 142.
    Clore, G.M., Robien, M.A., and Gronenborn, A.M. (1993) Exploring the limits of precision and accuracy of protein structures determined by nuclear magnetic resonance spectroscopy. J Mol Biol, 231, 82.PubMedCrossRefGoogle Scholar
  143. 143.
    Faber, H.R. and Matthews, B.W. (1990) A mutant T4 lysozyme displays five dif­ferent crystal conformations. Nature, 348, 263.PubMedCrossRefGoogle Scholar
  144. 144.
    Fiser, A. (2008) In Ridgen, D.J. (ed.), From Protein Structure to Function with Bioinformatics. Springer, pp. 57–81.Google Scholar

Copyright information

© Springer Science+Business Media, LLC 2010

Authors and Affiliations

  • Andras Fiser
    • 1
  1. 1.Department of Systems and Computational Biology & Department for BiochemistryAlbert Einstein College of MedicineBronxUSA

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