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Classification: understanding the diversity and principles of

Classification: understanding the diversity and principles of. protein structure and function. Tool: structure comparison. MCSG 2001 structures. Why compare protein structures?. Learn about – structure-function relationships – evolution – common building blocks – motifs

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Classification: understanding the diversity and principles of

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  1. Classification: understanding the diversity and principles of protein structure and function Tool: structure comparison MCSG 2001 structures

  2. Why compare protein structures? • Learn about – structure-function relationships – evolution – common building blocks – motifs • Make order out of the universe of protein structures • Help structure prediction Inge Jonassen

  3. Structure Comparison Growth factor Cytokine • Evolutionary relationship • Structure classification

  4. 9% sequence identity Shapiro & Harris, 2000

  5. Gerstein

  6. Strategies • Bottom Up find local matches first, then solve the combinatorial problem to identify the largest cluster of matching substructures (e.g., Dali, CE, etc.) • Top Down find a rough global alignment first, then use a refinement procedure to identify details of local matches (e.g., 3D look-up, subgraph isomorphism, etc.)

  7. Types of substructure used • Atom/atom group • Residue • Fragment • Secondary structure element (SSE) • Structure described by elements of the chosen type (e.g. molecular surface)

  8. Gerstein

  9. Gerstein

  10. Gerstein

  11. SAP (iterated DDP)

  12. DDP

  13. Dali

  14. Dali’s idea

  15. 3D Lookup Holm & Sander (1995)

  16. 3D Lookup

  17. Structure Comparison Tools • DALI ( http://www2.ebi.ac.uk/dali/ ) • CE ( http://cl.sdsc.edu/ ) • VAST (http://www.ncbi.nlm.nih.gov/Structure/VAST/vast.html ) • Prosup ( http://www.came.sbg.ac.at ) • FLASH (http://thr.ibms.sinica.edu.tw/flash/)

  18. Complication: alternative alignments

  19. Results of different methods on the comparison of Azurin (1azc:A) vs plastocyanin (1plc)

  20. Complication: permutation

  21. Circular Permutation (CP) B N A C B A C N C D C D ..A..B..C..D.. ..C..D..A..B..

  22. A real example of CP C N N C 1nls (Concanavalin) 1led (Lectin)

  23. FLASH’s algorithm SSE matching: Angle-distance map:

  24. Greedy selection of distinct alignment solutions (1) g - f’ d - c’f - e’ e - d’ b - a’ c - b’ (2) c - e’ b - d’d - f’ (3) e - a’ f - b’g - c’ Optimal: Alternative:

  25. N C’ C N’ N C A B C D N’ C’ A D C B Scrambled Protein Pair “…few, if any, are able to detect permutations directly.” - Robert B. Russell (2002)

  26. Unique Capabilities: • alternative alignments allowing sub-domain motif (structural building block) discovery • permutation detection at all levels of complexity

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