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 Evolutionary relationship
Growth factor
Cytokine
Evolutionary relationship
Structure classification

4. 9% sequence identity
Shapiro & Harris, 2000

6. Gerstein

7. 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.)

8. 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)

9. Gerstein

10. Gerstein

11. Gerstein

12. SAP (iterated DDP)

13. DDP

14. Dali

15. Dali’s idea

16. 3D Lookup
Holm & Sander (1995)

17. 3D Lookup

18. Structure Comparison Tools
DALI ( )
CE ( )
VAST ( )
Prosup ( )
FLASH (

19. Complication: alternative alignments

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

24. Complication: permutation

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

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

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

29. 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’ g - f’
50.4 d c’
42.1 f e’
33.7 e d’
33.3 b a’
30.4 c b’
27.2
8.9
7.7
6.3
5.8
4.6
3.8
1.5
1.2 a
Optimal: Alternative:

30. Scrambled Protein Pair
“…few, if any, are able to detect permutations directly.”
- Robert B. Russell (2002)

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