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Building an Invisible Puzzle: Predicting Protein Structure and Function from Sequence

Building an Invisible Puzzle: Predicting Protein Structure and Function from Sequence . Matthew Perella January 31, 2013. Proteins. Abundance 20 Amino Acids Role in nearly all cellular processes Enzymes, hormones, signaling, immune system, muscle fibers, transporters 1.

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Building an Invisible Puzzle: Predicting Protein Structure and Function from Sequence

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  1. Building an Invisible Puzzle:Predicting Protein Structure and Function from Sequence Matthew Perella January 31, 2013

  2. Proteins • Abundance • 20 Amino Acids • Role in nearly all cellular processes • Enzymes, hormones, signaling, immune system, muscle fibers, transporters1 Levels of Protein Structure2 Nelson, D. L.; Cox, M. M., Priciples of Biochemistry. 5 ed.; W.H. Freeman and Company: New York, 2008. Image obtained from: primary protein structure | protein-pdb.com. http://proteinpdb.com/2011/10/04/primary-protein-structure/.

  3. Understanding Structure and Function • Proteomics • Characterize structures • Whole-genome sequencing (<1%) • Experimentally • X-Ray Crystallography • NMR Spectroscopy • Computational Prediction • Bioinformatics

  4. Research VinylphenolReductase Sequence MPLMTISDSVKDSLTKSEVVPTVIHDKSFLPKGFLTIQYDSGKEVALGNNIRPADSKNLPRIDFTLNLPSDASSTFNISKDDRFTLIVTDPDAPTRNDEKWSEYLHYLAVDVQLNTFNAENASSNDQLSTADLKGRTLYPYIGPGPPPKTGKHRYVFLLYKQTPGVTPEAPKDRPNWGTGIRGAGAAEYAEKYKLTPYAVNFFYAQNDQQ3 • Wine Spoilage • Brettanomycesbruxellensis • Vinylphenol Reductase3 • Vinylphenols • Ethylphenols • How?? 3. Tchobanov, I.; Gal, L.; Guilloux-Benatier, M. l.; Remiz, F.; Nardi, T.; Guzzo, J.; Serpaggi, V.; Alexandre, H., Partial vinylphenolreductase purification and characterization from Brettanomycesbruxellensis - Powered by Google Docs. European Federation of Microbiological Studies 2008.

  5. Sequence Databases • Protein Data Bank (PDB) • As of Wednesday, January 30th. There are 81,306 characterized structures in the PDB database4 • UniProtKB/Swiss-Prot • 538,849 reviewed sequences 29,266,939 unreviewed sequences5 • Only 77,110 have experimentally solved structures 4. RCSB PDB - Holdings Report. http://www.rcsb.org/pdb/statistics/holdings.do. 5. UniProtKB/Swiss-Prot Available at: http://ca.expasy.org/sprot/relnotes/relstat.html

  6. Classification Schemes • Gene Ontology (GO) • Secondary Structure • Structural Motifs • Family • CATH & SCOP • PROSITE • InterPro • Pfam Sandhya, S. R.; Jayaram, B., Proteins: Sequence to Structure and Function – Current Status. Current protein and peptide science 2010, (11), 498 – 514.

  7. Resources • Similar Sequence Searching • Multiple Sequence Alignments • Prediction • Secondary Structure • 3-D Model • Viewing and Editing Software Watson, J. D.; Laskowski, R. A.; Thornton, J. M., Predicting protein function from sequence and structural data. Current Opinion in Structural Biology 2005,15 (3), 275-284.

  8. Table 1: Bioinformatics Resource Function Analysis

  9. Methods of Prediction • Pattern Recognition • pattern recognition techniques are used to find sequences with high similarity in order to infer related structures and functions. • Ab Initio • prediction method used to create 3-D model to determine structural and functional information using only the sequence Lee, D.; Redfern, O.; Orengo, C., Predicting protein function from sequence and structure. Nat Rev Mol Cell Biol2007,8 (12), 995-1005.

  10. Sequence Similarity Searches Altschul, S.F., Madden, T.L., Schäffer, A.A., Zhang, J., Zhang, Z., Miller, W. & Lipman, D.J. (1997) "Gapped BLAST and PSI-BLAST: a new generation of protein database search programs." Nucleic Acids Res. 25:3389-3402. PubMed BLAST PSI-BLAST

  11. Multiple Alignment • MUSCLE • CLUSTALW • COBALT RC, E., MUSCLE multiple sequence alignment with high accuracy and high throughput. Nucleic Acids Res. 2012,32 (5), 1792-1797. Papadopoulos JS and Agarwala R (2007) COBALT: constraint-based alignment tool for multiple protein sequences, Bioinformatics 23:1073-79. PubMed.

  12. Template Secondary Structure Annotation

  13. Secondary Structure Prediction

  14. Secondary Structure Annotation

  15. 3-D Model Prediction with Template • PHYRE-2 • PSI-BLAST • Psi-pred and Diso-pred • Hidden Markov Model (HMM) • HMM alignment • 3-D models from known structures • Maximizing Thermodynamic Stability • Modelling insertions and deletions with loop library • Modelling of AA side chains using a rotamer library to minimize steric interferences Kelley, L. A. S. M., Protein structure prediction on the web: a case study using the Phyre server. Nature Protocols 2009,4, 364-371.

  16. Phyre2 Model Alignment Results Kelley, L. A. S. M., Protein structure prediction on the web: a case study using the Phyre server. Nature Protocols 2009,4, 364-371.

  17. 3-D Model Prediction

  18. Superimposed Structural alignment • Alignment of α-helices and β-sheets • Motif conservation • Infer similar function from homologues Kelley, L. A. S. M., Protein structure prediction on the web: a case study using the Phyre server. Nature Protocols 2009,4, 364-371.

  19. Prediction Analysis • QMEAN and SWISS-MODEL used to assess

  20. Models Superimposed on Template

  21. Resources • 1. BLAST References. http://blast.ncbi.nlm.nih.gov/Blast.cgi?CMD=Web&PAGE_TYPE=BlastDocs&DOC_TYPE=References. • 2. COBALT:Multiple Alignment Tool. http://www.ncbi.nlm.nih.gov/tools/cobalt/cobalt.cgi?CMD=Doc. • 3. primary protein structure | protein-pdb.com. http://protein-pdb.com/2011/10/04/primary-protein-structure/. • 4. RCSB PDB - Holdings Report. http://www.rcsb.org/pdb/statistics/holdings.do. • 5. Kelley, L. A. S. M., Protein structure prediction on the web: a case study using the Phyre server. Nature Protocols 2009,4, 364-371. • 6. Lambert, C. L. N., De Bolle X, Depiereux E., ESyPred3D submitting form. 2012. • 7. Lee, D.; Redfern, O.; Orengo, C., Predicting protein function from sequence and structure. Nat Rev Mol Cell Biol2007,8 (12), 995-1005. • 8. Linding, R. e. a., Protein disorder prediction: Implications for structural proteomics. EMBL - Biocomputing unit: 2012. • 9. Nelson, D. L.; Cox, M. M., Priciples of Biochemistry. 5 ed.; W.H. Freeman and Company: New York, 2008. • 10. RC, E., MUSCLE multiple sequence alignment with high accuracy and high throughput. Nucleic Acids Res. 2012,32 (5), 1792-1797. • 11. Sandhya, S. R.; Jayaram, B., Proteins: Sequence to Structure and Function – Current Status. Current protein and peptide science 2010, (11), 498 – 514. • 12. Shenoy, S. R.; Jayaram, B., Proteins: sequence to structure and function--current status. Curr Protein PeptSci2010,11 (7), 498-514. • 13. Tchobanov, I.; Gal, L.; Guilloux-Benatier, M. l.; Remiz, F.; Nardi, T.; Guzzo, J.; Serpaggi, V.; Alexandre, H., Partial vinylphenolreductase purification and characterization from Brettanomycesbruxellensis - Powered by Google Docs. European Federation of Microbiological Studies 2008. • 14. Watson, J. D.; Laskowski, R. A.; Thornton, J. M., Predicting protein function from sequence and structural data. Current Opinion in Structural Biology 2005,15 (3), 275-284.

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