Similarity Search in Protein Databases

1. Similarity Search in Protein Databases David Hoksza, hoksza@ksi.mff.cuni.cz Supervisor: Tomáš Skopal, skopal@ksi.mff.cuni.cz KSI MFF UK

2. Thesis Contributions • Protein sequence similarity • metric indexing approach • sequential approach • speedup within existing similarity model • Protein structure similarity • nonalignment-based similarity approach • alignment-based similarity approach • similarity modelling itself

3. Protein structure & Motivation • Transportation, building, signalling, catabolism, ... • Molecule consisting of 20 types of amino acids (AA) • Central dogma of molecular biology • DNA → RNA → protein • Proteins’ 3D interactions secure biological function • protein structure similarity → biological function similarity • protein sequence similarity → protein structure similarity • Source: http://en.wikipedia.org/wiki/File:Main_protein_structure_levels_en.svg

4. Protein Sequence Similarity • Edit distance • minimal number of editing operations (insert/update/delete) needed for converting one sequence to the other • alignment • Weighted edit distance • scoring matrix (PAM, BLOSSUM, …) • amino acids’ mutation probability • affine gap penalty system • global alignment • dynamic programming - Needleman-Wunsch (NW) algorithm • local alignment • dynamic programming - Smith-Waterman (SW) algorithm • the locality leads to nonmetric measures

5. Metric Indexing Approach • Using metric access methods (MAMs) • organize objects into regions for effective filtering • require metric distance function • Distance function • E-value with SW • standard in biological databases • statistical relevance • dealing with • reflexivity, symmetry, triangular inequality (Trigen) D. Hoksza, T. Skopal. Index-Based Approach to Similarity Search in Protein and Nucleotide Databases. DATESO 2007

6. Metric Indexing Approach • Swissprot database • 3,000 DB sequences • 100 query sequences D. Hoksza, T. Skopal. Index-Based Approach to Similarity Search in Protein and Nucleotide Databases. DATESO 2007

7. Sequence-Based Approach • Speeding up distance computation itself • Skipping common parts in the DP matrix • context dependency problem • prefixes • database sort • skipping common prefixes • prefix ratio (PR) = speedup • suffixes • database division D. Hoksza. Improved Alignment of Protein Sequences Based on Common Parts, ISBRA 2008, LNCS

8. Sequence-Based Approach • Uniprot database D. Hoksza. Improved Alignment of Protein Sequences Based on Common Parts, ISBRA 2008, LNCS

9. Protein Structure Similarity • Nonalignment-based approach • indexing • feature extraction • simple or ad-hoc similarity measure • Alignment-based approach • sequential scan • feature extraction • alignment • superposition (3D transformation) • similarity measure • RMSD, TM-score • Quality criterion • classification accuracy (SCOP hierarchical classification)

10. Density-Based Feature Extraction • Features • n-dimensional vectors of real numbers • AA ≈ viewpoint → VPT (viewpoint tag) • sDens • density of AAs in rings of predefined width • sRad • widths of rings containing predefined percentage ofAAs D. Hoksza. DDPIn: Distance and Density-Based Protein Indexing, CIBCB 2009, IEEE

11. Nonalignment-Based Approach • One-step search • database creation • AAs → feature vectors • indexing using weighted L2 metric and MAM • querying • AAs → feature vectors • feature vector → query object • results’ merging • SCOP classification • Two-step search • 2 one-step searches • results’ comparison • rescoring using Smith-Waterman • SCOP classification D. Hoksza. DDPIn: Distance and Density-Based Protein Indexing, CIBCB 2009, IEEE

12. Alignment-Based Approach D. Hoksza, J. Galgonek. Density-Based Classification of Protein Structures Using Iterative TM-score, BIBMW 2009, IEEE D. Hoksza, J. Galgonek. Alignment-Based Extension to DDPIn Feature Extraction, IJCB, ACTA Press, 2010

13. Alignment-Based Approach • Feature extraction • AAs → feature vectors • density-based feature extraction • Alignment (amino acid matching) • Smith-Waterman alignment • distance between feature vectors → scoring matrix • modified variable gap penalty system • Superposition + scoring • RMSD • TM-score • reducing number of initial states • iterative dynamic programming with belt-based restriction D. Hoksza, J. Galgonek. Density-Based Classification of Protein Structures Using Iterative TM-score, BIBMW 2009, IEEE D. Hoksza, J. Galgonek. Alignment-Based Extension to DDPIn Feature Extraction, IJCB, ACTA Press, 2010

14. Alignment-Based Approach - Indexing • Indexability measures • intrinsic dimensionality • objects’ distribution • ball overlap factor (BOF) • ball regions’ separation • T-error • nontriangular triplets • Semimetrization • reranking • Metrization • Trigen J. Galgonek, D. Hoksza. On the Effectiveness of Distances Measuring Protein Structure Similarity, SISAP 2009, IEEE

15. Conclusion • Protein sequence search • indexing • data domain exploration • speeding distance computation • 20% speedup • expected speedup growth • Protein structure search • nonalignment-based • best accuracy on all SCOP levels • alignment-based • best accuracy on superfamily and fold SCOP levels • indexing possibilities • comparison with nonalignment-based

16. Publications D. Hoksza, T. Skopal Index-Based Approach to Similarity Search in Protein and Nucleotide Databases. DATESO 2007 D. Hoksza Improved Alignment of Protein Sequences Based on Common Parts ISBRA 2008, LNCS D. Hoksza DDPIn: Distance and Density-Based Protein Indexing CIBCB 2009, IEEE D. Hoksza , J. Galgonek Density-Based Classification of Protein Structures Using Iterative TM-score BIBMW 2009, IEEE J. Galgonek, D. Hoksza On the Effectiveness of Distances Measuring Protein Structure Similarity SISAP 2009, IEEE D. Hoksza , J. Galgonek Alignment-Based Extension to DDPIn Feature Extraction IJCB, ACTA Press, 2010