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CASP 5

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CASP 5. Fifth Meeting on the Critical Assessment of Techniques for Protein Structure Prediction Robert Langlois. Purpose. Establish in structure prediction from sequence Capabilities Limitations Accomplished by analysis of a large number of blind predictions. Prediction Categories.

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CASP 5

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  1. CASP 5 Fifth Meeting on the Critical Assessment of Techniques for Protein Structure Prediction Robert Langlois

  2. Purpose • Establish in structure prediction from sequence • Capabilities • Limitations • Accomplished by analysis of a large number of blind predictions

  3. Prediction Categories • CASP 5 • Comparative Modeling • Fold Recognition • New Fold methods • CAFASP 3 • Automated Servers

  4. Category Target Overlap Comparative Modeling Fold Recognition Ab Initio

  5. Comparative Modeling • Exploit evolutionary relationships to produce 3D structures • Has not changed in a few decades • General Protocol • Start by identifying the template • Align sequences of target and template • Model conserved then diverged regions • Assign side chain conformations, refine model

  6. Scoring • GDT-TS • Global distance test • Number of Cα in prediction not deviating more than di from Cα in the target • Under the condition of optimal super-position • RMSD of Cα • Percent of Correctly Aligned Residues

  7. Comparative Modeling Results • Over 39 proteins, consisting of 51 domains • Able to identify templates with 6% identity • Improvement of CASP4, <17% identity • Top 5 groups – Initial predictions • Murzin: Knowledge-based personal approach • Bujnicki-Janusz: Automatic servers • VENCLOVAS: Multiple sequence alignment • Ginalski: Automatic servers • GeneSilico

  8. Group Results cont. 448: Murzin 425: VENCLOVAS 020: Bujnicki 453: Ginalski 517: GeneSilico

  9. Overall Results • Servers better than most human predictors • 3D Shotgun meta-predictor • Baker’s ROBETTA server • However, no group was able to optimize • I.e. create many good models but cannot pick the best • No model comes significantly closer to target than the template

  10. Overall Results cont.

  11. CM Conclusion • Successes • Matching template to target • Performance of different methods has leveled • Failures • Cannot produce model, closer than template • Cannot model features not inherited • Future: select the best of several models

  12. Fold Recognition • Common approaches: taxonometric (SVM, NN.), threading, homology modeling • Combines fold recognition, comparative modeling, and de novo approaches

  13. Fold Recognition Methods • Template based combines • Correct template, comparative modeling and fold recognition servers • Refinement, available programs, and manual inspection • Ginalski • Fragment Assembly: Ab initio • Rosetta: identify small fragments from a library of existing structures • TOUCHSTONE: conserved contacts & threading

  14. Scoring • Livermore: GDT_TS, SOV_O, and LGA_Q • 3 structural superposition, 2 sequence depend • Incorporate scores from: • Dali: http://www.ebi.ac.uk/dali/ • CE: http://cl.sdsc.edu/ce.html • Mammoth: http://icb.mssm.edu/services/… • Dali & CE compare intra molecular Cα geometries • Mammoth: structural alignments independent of contact maps, depend on unit vector RMSD distances

  15. Fold Recognition Results • Top 3: Outperform the Rest • Baker – comparative modeling and ab initio • Ginalski – combine servers and manual inspection • Rychlewski – meta-server 3D Jury

  16. Top 20 Predictors

  17. Example: Rossmann-like α/β

  18. Multi-domain Failures

  19. Prediction Beats Template

  20. Unrealistic Models: Scoring Well

  21. Conclusions • While overall scores are higher than CASP4 • Does it reflect: better predictions or larger database? • Automatic servers nearly reach manual predictions

  22. New Fold Techniques • Ab Initio Folding Engine • Metropolis Rule • Potentials • Successful Groups use: • Fragment Methods • Contact Maps

  23. Scoring • RMSD, LCS, SOV, GDT_TS, Visual • GDT_TS agreed best with visual inspection • LCS – CASP3 holdover • Sequence dependent structural alignment

  24. Example (NF): H. influenzae

  25. Example (NF): E. coli

  26. Visual Table Results

  27. Summary of Methods

  28. Discussion • Fragment methods: better at choosing fragments than assembling them. • Automatic Servers similar performance • PROTINFO-AB, I-site/Bystroff, BAKER-ROBETTA • 20 out of 25 groups use PSI-PRED

  29. Conclusions • Coordinate Predictions • Impressive accuracy • Shows great progress in understanding folds • Convergence of fold recognition • Fragment: template library construction • Secondary Structure • Have reached limits

  30. Conclusions cont. • Residue-Residue Contacts • Very limited improvement • Fragment templates, better accuracy • Not accurate enough to build a model from scratch

  31. References Aloy, P., A. Stark, et al. (2003). "Predictions Without Templates: New Folds, Secondary Structure, and Contacts in CASP5." PROTEINS: Structure, Function, and Genetics 53: 436-456. Kinch, L. N., J. O. Wrabl, et al. (2003). "CASP5 Assessment of Fold Recognition Target Predictions." PROTEINS: Structure, Function, and Genetics 53: 395-409. Tramontano, A. and V. Morea (2003). "Assessment of Homolgy-Based Predictions in CASP5." PROTEINS: Structure, Function, and Genetics 53: 352-368.

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