1. Ferhat Ay, Tamer Kahveci & Valerie de-Crecy Lagard 4/17/20151 Ferhat Ay www.cise.ufl.edu/~fay

2. Metabolic Pathways 4/17/20152 Ferhat Ay

3. What and Why? 4/17/20153Ferhat Ay Metabolic Pathway Alignment Finding a mapping of the entities of the pathways C2 C3 C4 C5 R1R2 C1 E1E2 C2C4 R1R2 C1 C5 E1 E2 Applications ○ Drug Target Identification ○ Metabolic Reconstruction ○ Phylogeny Prediction

4. Challanges 4/17/20154 Ferhat Ay E1E2E3 E4 E1E2E3 Graph Alignment  Even after Abstraction Metabolic Pathway Alignment problem is NP Complete!  Existing Algorithms  Heymans et al. (2003)  Clemente et al. (2005)  Pinter et al. (2005)  Singh et al. (2007)  ….  Abstraction is a problem ! E1 C1 C2 E2 C3 C4 E3 E4 E1 C1 E2 C3 E3 - Where are the compounds? - E1  C1  E2 or E1  C2  E2 ?  Pathway Alignment is hard ! Abstraction

5. Outline 4/17/20155 Ferhat Ay  Graph Model of Pathways  Consistency of an Alignment  Homological & Topological Similarities  Eigenvalue Problem  Similarity Score  Experimental Results

6. Non-Redundant Graph Model 4/17/20156 Ferhat Ay Pyruv. 1.2.4.1 Lip-EThPP R0014 S-Ac 2-ThP A-CoA Di-hy R7618R3270 R2569 2.3.1.12 1.8.1.4

7. Consistency 4/17/20157 Ferhat Ay 1- Align only the entities of the same type (compatible) R1R2 C1C2 R1 C1 2- The overall mapping should be 1-1 R1 R2 R3

8. Consistency 4/17/20158 Ferhat Ay C3 C2 C5 C4 R1R2 C1 C2C4 R1R2 C1 C5 3- Align two entities u i, v i only if there exists an aligned entity pair u j, v j such that u j and v j are on the reachability paths of u i and v i respectively. Aligned Entities Backward Reachability Path Forward Reachability Path

9. Problem Statement 4/17/20159 Ferhat Ay Given a pair of metabolic pathways, our aim is to find the consistent alignment (mapping) of the entities (enzymes, reactions, compounds) such that the similarity between the pathways (SimP score) is maximized.

10. 4/17/201510 Ferhat Ay Pairwise Similarities (Homology of Entities)

11. Pairwise Similarities (Homology) 4/17/201511 Ferhat Ay  Enzyme Similarity (SimE) Hierarchical Enzyme Similarity - Webb EC.(2002) Information-Content Enzyme Similarity - Pinter et al.(2005)  Compound Similarity (SimC) Identity Score for compounds SIMCOMP Compound Similarity – Hattori et al.(2003)

12. Pairwise Similarities 4/17/201512 Ferhat Ay  Reaction Similarity (SimR) E1 R1 C3 C1 C2 R2 C6 C4 C7 C5 E2 E3 SimR (R1,R2) = Enzymes max ( SimE (E1,E3), SimC (E2,E3) ) Input Compounds + max ( SimC (C1,C4), SimC (C2,C4) ) Output Compounds + max ( SimC (C3,C5), SimC (C3,C6), SimC (C3,C7) ) SimR (R1,R2) = Enzymes max ( SimE (E1,E3), SimC (E2,E3) ) Input Compounds + max ( SimC (C1,C4), SimC (C2,C4) ) Output Compounds + max ( SimC (C3,C5), SimC (C3,C6), SimC (C3,C7) )

13. 4/17/201513 Ferhat Ay Topological Similarity (Topology of Pathways)

14. Neighborhood Graphs 4/17/201514 Ferhat Ay C4 C5 C6 C7 R1 R2 C1 E2 R3R4 E1 E3 C3 C2 C9 C8 E1E2E3 Enzymes R2 R3 R1 R4 Reactions C1 C3 C2 C4 C5 C6 C7 C8 C9 Compounds

15. Topological Similarities 4/17/201515 Ferhat Ay R2 R3 R1 R4 R1R3 R4 R5 |R| = 4 BN (R3)= {R1,R2} FN (R3)= {R4} BN (R3)= {R1} FN (R3)= {R4,R5} (|R| |R| ) x (|R| |R| ) = 16 x 16 A R matrix R1-R1…R2-R1…R4-R4…R4-R5.... R3 -R3 1 / 40 0 0 ….. A R [R3,R3][R2,R1] = 1 = 1 2*1 + 1*2 4

16. Problem Formulation 4/17/201516 Ferhat Ay R2 R3 R1 R4 R5 R6 R7 R8 R3 R1 R2 R5R7 R8 Focus on R3 – R3 matching Iteration 1: Support of aligned first degree neighbors addedIteration 2: Support of aligned second degree neighbors added Iteration 3: Support of aligned third degree neighbors added Iteration 0: Only pairwise similarity of R3 and R3

17. 4/17/201517 Ferhat Ay Initial Reaction Similarity Matrix H R 0 Vector 0.1 1.0 0.2 0.9 0.3 0.5 0.8 0.8 0.5 1.0 0.4 0.3 H R s Vector Final Reaction Similarity Matrix 0.2 1.0 0.4 0.6 0.2 0.3 0.6 0.9 0.6 0.9 0.5 Power Method Iterations 0.5 1.0 0.4 0.3 0.5 0.8 0.1 1.0 0.2 0.9 0.6 0.9 0.5 0.2 0.3 0.6 0.9 0.2 1.0 0.4 0.6 Problem Formulation 0.5 1.0 0.4 0.3 0.5 0.8 0.1 1.0 0.2 0.9 0.6 0.9 0.5 0.2 0.3 0.6 0.9 0.2 1.0 0.4 0.6

18. Max Weight Bipartite Matching 4/17/201518 Ferhat Ay  Six Possible Orderings ONLY 3 ARE UNIQUE ○ Reactions First ○ Enzymes First ○ Compounds First  R First Pruning R1 R2 R3 R1 R3 R2 C1 C2 C3 C4 C2 C3 E1 E2 E3 E1 E2 Consistency Assured ! Weighted Edges Aligned Entities Inconsistent Edges

19. Alignment Score ( SimP ) 4/17/201519 Ferhat Ay C2 C3 C4 C5 R1R2 C1 C2C4 R1R2 C1 C5 0 =< SimP <= 1 SimP =1 for identical pathways SimP =  Sim(C1) + Sim(C2) +Sim(C4) + ( 1 –  Sim(E1) + Sim(E2) 3 2 E1 E2

20. Outline 4/17/201520 Ferhat Ay  Graph Model of Pathways  Consistency of an Alignment  Homological & Topological Similarities  Eigenvalue Problem  Similarity Score  Experimental Results

21. Impact of Alpha 4/17/201521 Ferhat Ay  = 0  Only pairwise similarities of entities - No iterations  = 1  Only topology of the graphs  = 0.7 is good !

22. Alternative Entities & Paths 4/17/201522 Ferhat Ay Kim J. et al. (2007) Eukaryotes (e.g. H.Sapiens)  Mevalonate Path Bacterias (e.g. E.Coli)  Non-Mevalonate Path Kuzuyama T. et al. (2006)

23. Phylogeny Prediction 4/17/201523 Ferhat Ay Thermoprotei Eukaryota Archaea NCBI Taxonomy Our Prediction Deuterostomia

24. Effect Of Consistency Restriction 4/17/201524 Ferhat Ay

25. Running Time 4/17/201525 Ferhat Ay

26. 4/17/2015 Ferhat Ay 26 For source code and more information: www.cise.ufl.edu/~fay

27. 4/17/2015 Ferhat Ay 27

28. Error Tolerance 4/17/201528 Ferhat Ay

29. Pylogenetic Reconstruction 4/17/201529Ferhat Ay

30. Effect Of Consistency Restriction 4/17/201530Ferhat Ay

31. Z-Score Calculation 4/17/201531Ferhat Ay

32. E1 C1 C2 E2 C3 C4 E3 E4 Challanges 4/17/201532 Ferhat Ay E1E2E3 E4 E1 C1 E2 C3 E3E1E2E3 - Where are the compounds? - E1  C1  E2 or E1  C2  E2 ? Pathway 1 Pathway 2 Abstraction is a Problem! Pathway 1 Abstracted Pathway 2 Abstracted NO AbstractionAbstraction Alignment Problem is NP Complete !