Machine Learning in the Study of Protein Structure

1. Machine Learning in the Study of Protein Structure Rui Kuang Columbia University Candidacy Exam Talk May 5th, 2004 Committee: Christina S. Leslie (advisor), Yoav Freund, Tony Jebara

2. Table of contents • Introduction to protein structure and its prediction • HMM, SVM and string kernels • Machine learning in the study of protein structure • Protein ranking • Protein structural classification • Protein secondary structural and conformational state prediction • Protein domain segmentation • Conclusion and Future work

3. Introduction • HMM, SVM and string kernels • Topics • Conclusion and future work Part 1: Introduction to Protein Structure and Its Prediction Thanks to Carl-Ivar Branden and John Tooze

4. Why study protein structure • Protein– Derived from Greek word proteios meaning “of the first rank” in 1838 by Jöns J. Berzelius • Crucial in all biological processes • Function depends on structure structure can help us to understand function

5. How to Describe Protein Structure • Primary structure: amino acid sequence • Secondary structure: local structure elements • Tertiary structure: packing and arrangement of secondary structure, also called domain • Quaternary structure: arrangement of several polypeptide chains

6. Secondary Structure : Alpha Helix hydrogen bonds between C’=O at position n and N-H at position n+i (i=3,4,5)

7. Secondary Structure : Beta Sheet Antiparallel Beta Sheet Parallel Beta Sheet We can also have a mix of both.

8. Secondary Structure : Loop Regions • Less conserved structure • Insertions and deletions are more often • Conformations are flexible

9. Tertiary Structure Phi – N - bond Psi – -C’ bond

10. Phi-Psi angle distribution

11. Protein Domains • A polypeptide chain or a part of a polypeptide chain that can fold independently into a stable tertiary structure.

12. Determination of Protein Structures • Experimental determination (time consuming and expensive) • X-ray crystallography • Nuclear magnetic resonance (NMR) • Computational determination [Schonbrun 2002 (B2)] • Comparative modeling • Fold recognition ('threading') • Ab initio structure prediction (‘de novo’)

13. Sequence, Structure and Function [Domingues 2000 (B1)] Sequence (1,000,000) • >30% sequence similarity suggests strong structure similarity • Remote homologous proteins can also share similar structure Structure (24,000): discrete groups of folds with unclear boundaries • Function associated with different structures • Super-family with the same fold can evolve into distinct functions. • 66% of proteins having similar fold also have a similar function Function (Ill-defined) Picture due to Michal Linial

14. Introduction • HMM, SVM and string kernels • Topics • Conclusion and future work Part 2: Hidden Markov Model, Support Vector Machine and String Kernels K( , ) Thanks to Nello Cristianini

15. Hidden Markov Models for Modeling Protein [Krogh 1993(B3)] Alignment Maximum Likelihood Or Maximum a posteriori HMM If we don’t know the alignment, use EM to train HMM.

16. Hidden Markov Models for Modeling Protein [Krogh 1993(B3)] • Probability of sequence x through path q • Viterbi algorithm for finding the best path • Can be used for sequence clustering, database search…

17. Support Vector Machine [Burges 1998(B4)] • Relate to structural risk minimization • Linear-separable case • Primal qp problem Minimize subject to • Dual convex problem Minimize subject to &

18. Support Vector Machine [Burges 1998(B4)] • Kernel: one nice property of dual qp problem is that it only involves the inner product between feature vectors, we can define a kernel function to compute it more efficiently • Example:

19. String Kernels for Text Classification [Lodhi 2002(M2)] • String subsequence kernel –SSK : • A recursive computation of SSK has the complexity of the computation O(n|s||t|). It is quadratic in terms of the length of input sequences. Not practical.

20. Introduction • HMM, SVM and string kernels • Topics • Conclusion and future work Part 3 Machine learning in the study of protein structure 3.1 Protein ranking 3.2 Protein structural classification 3.3 Protein secondary structure and conformational state prediction 3.4 Protein domain segmentation

21. Smith-Waterman • SAM-T98 • BLAST/PSI-BLAST • Rank Propagation Part 3.1 Protein Ranking Please!!! Stand in order

22. Local alignment: Smith-Waterman algorithm • For two string x and y, a local alignment with gaps is: • The score is: • Smith-Waterman score: Thanks to Jean Philippe

23. BLAST [Altschul 1997 (R1)]: a heuristic algorithm for matching DNA/Protein sequences • Idea: True matches are likely to contain a short stretch of identity AKQ KQD QDY DYY YYY… AKQSKQ.. KQDAQD.. QDY .. DYY .. YYY… Protein Database Neighbor mapping AKQDYYYYE… cut Search match substitution score>T Query: ………DYY……………… Target: …ASDDYYQQEYY… Extend match Extend match

24. PSI-BLAST: Position-specific Iterated BLAST [Altschul 1997 (R1)] • Only extend those double hits within a certain range. • A gapped alignment uses dynamic programming to extend a central pair of aligned residues in both directions. • PSI-BLAST can takes PSSM as input to search database

25. SAM-T98 [Karplus 1999 (C3)] Iterate 4 rounds NR Protein database Query sequence Blast search Build alignment with hits search Profile/Alignment HMM

26. Local and Global Consistency [Zhou 2003 (M1)] • Affinity matrix • D is a diagonal matrix of sum of i-th row of W • Iterate • F* is the limit of seuqnce {F(t)}

27. Rank propagation [Weston 2004 (R2)] • Protein similarity network: • Graph nodes: protein sequences in the database • Directed edges: a exponential function of the PSI-BLAST e-value (destination node as query) • Activation value at each node: the similarity to the query sequnce • Exploit the structure of the protein similarity network

28. Result [Weston 2004 (R2)]

29. Fisher Kernel • Mismatch Kernel • ISITE Kernel • SVM-Pairwise • EMOTIF Kernel • Cluster Kernels Part 3.2 Protein structural classification Where are my relatives?

30. SCOP Fold Superfamily Negative Test Set Negative Training Set Family Positive Test Set Positive Training Set SCOP[Murzin 1995 (C1)] Family : Sequence identity > 30% or functions and structures are very similar Superfamily : low sequence similarity but functional features suggest probable common evolutionary origin Common fold : same major secondary structures in the same arrangement with the same topological connections

31. CATH[Orengo 1997 (C2)] • Class Secondary structure composition and contacts • Architecture Gross arrangement of secondary structure • Topology Similar number and arrange of secondary structure and same connectivity linking • Homologous superfamily • Sequence family

32. Fisher Kernel [Jaakkola 2000 (C4)] • A HMM (or more than one) is built for each family • Derive feature mapping from the Fisher scores of each sequence given a HMM H1:

33. SVM-pairwise [Liao 2002 (C5)] • Represent sequence P as a vector of pairwise similarity score with all training sequences • The similarity score could be a Smith-Waterman score or PSI-BLAST e-value.

34. Mismatch Kernel [ Leslie 2002 (C6)] AKQ KQD QDY DYY YYY… Implementation with suffix tree achieves linear time complexity O(||mkm+1(|x|+|y|)) AKQDYYYYE… AKQ … CKQ AKY … DKQ AAQ ( 0 , … , 1 , … , 1 , … , 1 , … , 1 , … , 0 ) AAQAKQDKQEKQ AKQ

35. EMOTIF Kernel [Ben-Hur 2003 (C8)] • EMOTIF TRIE built from eBLOCKS [Nevill-manning 1998 (C7)] • EMOTIF feature vector: where is the number of occurrences of the motif m in x

36. I-SITE Kernel [Hou 2003 (C10)] • Similar to EMOTIF kernel I-SITE kernel encodes protein sequences as a vector of the confidence level against structural motifs in the I-SITES library [Bystroff 1998 (C9)]

37. Cluster kernels [Weston 2004 (C11)] • Neighborhood Kernels Implicitly average the feature vectors for sequences in the PSI-BLAST neighborhood of input sequence (dependent on the size of the neighborhood and total length of unlabeled sequences) • Bagged Kernels Run bagged k-means to estimate p(x,y), the empirical probability that x and y are in the same cluster. The new kernel is the product of p(x,y) and base kernel K(x,y)

38. Results

39. PrISM • HMMSTR • PHD • PSI-PRED Part 3.3: Protein secondary structure and conformational state prediction Can we really do that?

40. PHD: Profile network from HeiDelberg [Rost 1993 (P1)] Accuracy: 70.8%

41. PSIPRED [Jones 1999 (P2)] Accuracy: 76.0%

42. Conformational State Prediction

43. PrISM [Yang 2003 (P3)] Prediction with this conformation library based on sequence and secondary structure similarity, accuracy: 74.6%

44. HMMSTR [Bystroff 2000 (P4)]: a Hidden Markov Model for Local Sequence-Structure Correlations in Proteins • I-sites motifs are modeled as markov chains and merged into one compact HMM to capture grammatical structure • The HMM can be used for Gene finding, secondary or conformational state prediction, sequence alignment… • Accuray: • secondary structure prediction: 74.5% • Conformational state prediction: 74.0%

45. Part 3.4: Protein domain segmentation • DOMAINATION • Pfam Database • Multi-experts Cut? where???

46. DOMAINATION [George 2002 (D1)] • Get a distribution of both the N- and C-termini in PSI-BLAST alignment at each position, potential domain boundaries with Z-score>2 • Acuracy: 50% over 452 multi-domain proteins

47. Pfam [Sonnhammer 1997 (D2)] • A database of HMMs of domain families • Pfam A: high quality alignments and HMMS built from known domains • Pfam B: domains built from Domainer algorithm from the remaining protein sequences with removal of Pfam-A domains

48. A multi-expert system from sequence information [Nagarajan 2003 (D3)] Intron Boundaries DNA DATA Seed Sequence blast search Sequence Participation Multiple Alignment Secondary Structure Entropy Neural Network Correlation Contact Profile Physio-Chemical Properties Putative Predictions

50. Results [Nagarajan 2003 (D3)]