MS bioinformatics - Project talk held on 01.04.2006

1. Benchmarking and Extension of Protein3DFit Nasir Mahmood

5. Simple case – two closely related proteins with the same number of amino acids. Structure alignment Problem A B Introduction Method Results Outlook T Find a transformation to achieve the best superposition

6. Structure Alignment Problem Two sets of Points in 3D space: A = (a1, a2, …, an) B = (b1, b2, …, bm) A(P) , B(Q): Optimal subsets with | A(P) |=| B(Q) |, Introduction Method Results Outlook Optimal rigid body transformation (calculated by Diamond (1998) method) Distance { d( A(P) - T( B(Q) ) ) } min T

12. Algorithm Intra-Molecular distance Seed Alignments (Fragments & Quartets) Next Best Frag Quartet 1 Quartet 2 .............. .............. Alignment Dynamic Programming i<N No Stop C α Match? increased Yes No Sup. Archive Yes Optimization Best Supp. Display Best Alignment Introduction Method Results Outlook Structures Superimpose

13. Intra-molecular Distance Matrices 1 2 3 4 5 . . . . . N 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 Structure A Structure B 1.4 3.0 0.7 1.9 0.0 4.7 0.0 2.9 0.0 0.0 2.1 0.3 0.0 3.1 0.6 2.9 0.0 0.0 0.0 0.4 0.0 5.9 0.0 2.3 1.4 3.0 0.7 1.9 0.0 4.7 0.0 2.9 2.1 0.3 0.0 3.1 0.6 2.9 0.0 0.0 0.4 0.0 5.9 0.0 2.3 0.4 0.0 5.9 0.0 2.3 3.1 0.6 2.9 0.0 0.6 2.9 0.0 1 2 3 4 5 ........................... N 0.0 0.0 0.0 1.4 3.0 0.0 1.9 0.0 4.7 0.0 2.9 0.0 0.0 2.1 0.3 0.0 3.1 0.6 2.9 0.0 0.0 0.0 0.4 0.0 5.9 0.0 2.3 1.4 1.4 1.4 1 2 3 4 5 ............................ M 1 2 3 4 5 . . . . . M i i+1 i+2 i+3 i+4 i+5 i+6 i+7 Introduction Method Results Outlook i i+1 i+2 i+3 i+4 i+5 i+6 i+7

14. Seed Alignments Extend Fragment Make Fragment Quartet Introduction Method Results Outlook

15. Algorithm Intra-Molecular distance Seed Alignments (Fragments & Quartets) Next Best Frag Quartet 1 Quartet 2 .............. .............. Alignment Dynamic Programming i<N No Stop C α Match? increased Yes No Sup. Archive Yes Optimization Best Supp. Display Best Alignment Introduction Method Results Outlook Structures Superimpose

18. Algorithm- Pitfalls Reference: 10 ‘difficult‘ structures from (Fischer et al.) obtained by Dali (Holm & Sander, 1993) , VAST (Madej et al., 1995) & CE (Shindyalov & Bourne, 1998) 187/3.2 211/3.4 100/1.2 1EDE:_ 1CRL:_ 7 116/2.9 108/2.0 82/1.7 70/1.1 4FGF:_ 1TIE:_ 10 94/4.1 98/3.5 74/2.5 52/1.1 2GMF:A 1BGE:B 9 264/3.0 286/3.8 284/3.8 129/1.2 1NSB:A 2SIM:_ 8 94/2.7 95/3.3 85/2.2 59/1.1 2RHE:_ 1CID:_ 6 69/1.9 81/2.3 71/1.9 54/1.2 1MOL:A 1CEW:I 5 85/2.9 _ 74/2.2 52/1.2 1PAZ:_ 2AZA:A 4 85/3.5 63/2.5 _ 42/1.1 2RHE:_ 3HLA:B 3 87/1.9 86/1.9 78/1.6 71/1.0 3HHR:B 1TEN:_ 2 _ _ 48/2.1 39/1.0 1UBQ:_ 1FXI:A 1 CE DALI VAST Protein3DFit Chain 2 Chain 1 No

19. Algorithm - Extension Introduction Method Results Outlook

20. C α Match increased Yes Intra-Mol distance based Seed Alignments (Fragments & Quartets) Next No Best Frag Quartet 1 Quartet 2 .............. .............. Alignment Dynamic Programming Optimization C α Matches ? Increase Yes No Improved? i<N Sup. Archive Yes No i<M Yes Yes No Optimization Stop Get Supp. Display Best Alignment Next No Superimpose Structures Superimpose

21. Similarity Score : similarity score used in DP :distance :distance resulting in half-maximal similarity M :maximum score for a match Source: Gerstein Levitt, 1998 Introduction Method Results Outlook

22. Quality Function Q score, ratio of no. of aligned residues & RMSD :number of matches (equivalent residues) :length of structure 1 & 2 respectively :empirical parameter measuring Relative significance of & RMSD Source: Krissinel & Henrich (2004) Introduction Method Results Outlook

24. Results source: 10 ‘difficult‘ structures from (Fischer et al.) obtained by Dali (Holm & Sander, 1993) , VAST (Madej et al., 1995) & CE (Shindyalov & Bourne, 1998). 39/1.0 71/1.0 42/1.1 52/1.2 54/1.2 59/1.1 100/1.2 129/1.2 52/1.1 70/1.1 Introduction Method Results Outlook 187/3.2 211/3.4 181/3.2 1EDE:_ 1CRL:_ 7 116/2.9 108/2.0 82/1.7 105/2.6 4FGF:_ 1TIE:_ 10 94/4.1 98/3.5 74/2.5 81/3.0 2GMF:A 1BGE:B 9 264/3.0 286/3.8 284/3.8 265/3.2 1NSB:A 2SIM:_ 8 94/2.7 95/3.3 85/2.2 91/2.6 2RHE:_ 1CID:_ 6 69/1.9 81/2.3 71/1.9 76/2.1 1MOL:A 1CEW:I 5 85/2.9 _ 74/2.2 80/2.3 1PAZ:_ 2AZA:A 4 85/3.5 63/2.5 _ 69/3.4 2RHE:_ 3HLA:B 3 87/1.9 86/1.9 78/1.6 82/1.7 3HHR:B 1TEN:_ 2 _ _ 48/2.1 59/2.9 1UBQ:_ 1FXI:A 1 CE DALI VAST Protein3DFit Chain 2 Chain 1 No

25. Results Introduction Method Results Outlook

26. CE Dali 3Dfit-old 3Dfit-ext Introduction Method Results Outlook

27. CE Dali 3Dfit-old 3Dfit-ext

28. 3Dfit-ext 3Dfit-old

31. Questions? Thanks a lot for your patience!