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11/9/05 Protein Structure Databases (continued) Prediction & Modeling

11/9/05 Protein Structure Databases (continued) Prediction & Modeling . Bioinformatics Seminars. Nov 10 Thurs 3:40 Com S Seminar in 223 Atanasoff Computational Epidemiology Armin R. Mikler, Univ. North Texas http://www.cs.iastate.edu/~colloq/#t3

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11/9/05 Protein Structure Databases (continued) Prediction & Modeling

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  1. 11/9/05Protein Structure Databases (continued) Prediction & Modeling D Dobbs ISU - BCB 444/544X: Protein Structure Databases - cont.

  2. Bioinformatics Seminars Nov 10 Thurs 3:40 Com S Seminarin 223 Atanasoff Computational Epidemiology Armin R. Mikler, Univ. North Texas http://www.cs.iastate.edu/~colloq/#t3 Nov 10 Thurs 4:10 EEOBSeminarin 210 Bessey Diversity and Evolution of Plant Immunity Genes: Insights from Molecular Population Genetics Peter Tiffin, Univ. of Minnesota http://www.cbs.umn.edu/tiffin/index.html D Dobbs ISU - BCB 444/544X: Protein Structure Databases - cont.

  3. Bioinformatics Seminars CORRECTION: Next week - Baker Center/BCB Seminars: (seminar abstracts available at above link) Nov 14 Mon 1:10 PM Doug Brutlag, Stanford Discovering transcription factor binding sites Nov 15 Tues 1:10 PM Ilya Vakser, Univ Kansas Modeling protein-protein interactions both seminars will be in Howe Hall Auditorium D Dobbs ISU - BCB 444/544X: Protein Structure Databases - cont.

  4. Protein Structure & Function:Analysis & Prediction Mon Protein structure: basics; classification,databases, visualization Wed Protein structure databases - cont. Thurs Lab Protein structure databases Protein structure analysis & prediction Fri Protein structure prediction Protein-nucleic acid interactions D Dobbs ISU - BCB 444/544X: Protein Structure Databases - cont.

  5. Reading Assignment (for Mon-Fri) • Mount Bioinformatics • Chp 10 Protein classification & structure prediction http://www.bioinformaticsonline.org/ch/ch10/index.html • pp. 409-491 • Ck Errata:http://www.bioinformaticsonline.org/help/errata2.html • Additional reading assignments for BCB 544: • Gene Prediction: Burge & Karlin 1997 JMB 268:78 Prediction of complete gene structures in human genomic DNA • Structure Prediction: Schueler-Furman…Baker, Science 310:638 Progress in modeling of protein structures and interactions D Dobbs ISU - BCB 444/544X: Protein Structure Databases - cont.

  6. Review last lecture:Protein Structure: Basics D Dobbs ISU - BCB 444/544X: Protein Structure Databases - cont.

  7. Protein Structure & Function • Amino acids characteristics • Structural classes & motifs • Protein functions & functional families • (not much - more on this later) • Classification • Databases • Visualization D Dobbs ISU - BCB 444/544X: Protein Structure Databases - cont.

  8. Amino Acids • Each of 20 different amino acids has different "R-Group," side chain attached to Ca D Dobbs ISU - BCB 444/544X: Protein Structure Databases - cont.

  9. Peptide bond is rigid and planar D Dobbs ISU - BCB 444/544X: Protein Structure Databases - cont.

  10. Hydrophobic Amino Acids D Dobbs ISU - BCB 444/544X: Protein Structure Databases - cont.

  11. Charged Amino Acids D Dobbs ISU - BCB 444/544X: Protein Structure Databases - cont.

  12. Polar Amino Acids D Dobbs ISU - BCB 444/544X: Protein Structure Databases - cont.

  13. Certain side-chain configurations are energetically favored (rotamers) Ramachandran plot: "Allowable" psi & phi angles D Dobbs ISU - BCB 444/544X: Protein Structure Databases - cont.

  14. Glycine is smallest amino acidR group = H atom • Glycine residues increase backbone flexibility because they have no R group D Dobbs ISU - BCB 444/544X: Protein Structure Databases - cont.

  15. Proline is cyclic • Proline residues reduce flexibility of polypeptide chain • Proline cis-trans isomerization is often a rate-limiting step in protein folding • Recent work suggests it also may also regulate ligand binding in native proteins -Andreotti D Dobbs ISU - BCB 444/544X: Protein Structure Databases - cont.

  16. Cysteines can form disulfide bonds • Disulfide bonds (covalent) stabilize 3-D structures • In eukaryotes, disulfide bonds are found only in secreted proteins or extracellular domains D Dobbs ISU - BCB 444/544X: Protein Structure Databases - cont.

  17. Globular proteins have a compact hydrophobic core • Packing of hydrophobic side chains into interior is main driving force for folding • Problem? Polypeptide backbone is highly polar (hydrophilic) due to polar -NH and C=O in each peptide unit; these polar groups must be neutralized • Solution? Form regular secondary structures, • e.g., -helix, b-sheet, stabilized by H-bonds D Dobbs ISU - BCB 444/544X: Protein Structure Databases - cont.

  18. Exterior surface of globular proteins is generally hydrophilic • Hydrophobic core formed by packed secondary structural elements provides compact, stable core • "Functional groups" of protein are attached to this framework; exterior has more flexible regions (loops) and polar/charged residues • Hydrophobic "patches" on protein surface are often involved in protein-protein interactions D Dobbs ISU - BCB 444/544X: Protein Structure Databases - cont.

  19. Protein Secondary Structures • Helices • Sheets • Loops • Coils D Dobbs ISU - BCB 444/544X: Protein Structure Databases - cont.

  20. helix: stabilized by H-bonds between every ~ 4th residue in backbone C = black O = red N = blue D Dobbs ISU - BCB 444/544X: Protein Structure Databases - cont.

  21. Certain amino acids are "preferred" & others are rare in helices • Ala, Glu, Leu, Met = good helix formers • Pro, Gly Tyr, Ser = very poor • Amino acid composition & distribution varies, depending on on location of helix in 3-D structure D Dobbs ISU - BCB 444/544X: Protein Structure Databases - cont.

  22. -sheets - also stabilized by H-bonds between back bone atoms Anti-parallel Parallel D Dobbs ISU - BCB 444/544X: Protein Structure Databases - cont.

  23. Loops • Connect helices and sheets • Vary in length and 3-D configurations • Are located on surface of structure • Are more "tolerant" of mutations • Are more flexible and can adopt multiple conformations • Tend to have charged and polar amino acids • Are frequently components of active sites • Some fall into distinct structural families (e.g., hairpin loops, reverse turns) D Dobbs ISU - BCB 444/544X: Protein Structure Databases - cont.

  24. Coils • Regions of 2' structure that are not helices, sheets, or recognizable turns • Intrinsically disordered regions appear to play important functional roles D Dobbs ISU - BCB 444/544X: Protein Structure Databases - cont.

  25. Globular proteins are built from recurring structural patterns • Motifs or supersecondary structures = • combinations of 2' structural elements • Domains = combinations of motifs • Independently folding unit (foldon) • Functional unit D Dobbs ISU - BCB 444/544X: Protein Structure Databases - cont.

  26. Simple motifs combine to form domains D Dobbs ISU - BCB 444/544X: Protein Structure Databases - cont.

  27. 6 main classes of protein structure • 1) a Domains • Bundles of helices connected by loops • 2)  Domains • Mainly antiparallel sheets, usually with 2 sheets forming sandwich • 3) aDomains • Mainly parallel sheets with intervening helices, also mixed sheets • 4)  aDomains • Mainly segregated helices and sheets • 5) Multidomain (a   • Containing domains from more than one class • 6) Membrane & cell-surface proteins D Dobbs ISU - BCB 444/544X: Protein Structure Databases - cont.

  28. -domain structures: 4-helix bundles D Dobbs ISU - BCB 444/544X: Protein Structure Databases - cont.

  29. -sheets: up-and-down sheets & barrels D Dobbs ISU - BCB 444/544X: Protein Structure Databases - cont.

  30. a-domains: leucine-rich motifs can form horseshoes D Dobbs ISU - BCB 444/544X: Protein Structure Databases - cont.

  31. New today:Protein Structure Databases ClassificationVisualization Protein Structure Prediction Secondary structure Tertiary structure D Dobbs ISU - BCB 444/544X: Protein Structure Databases - cont.

  32. Protein sequence databases • UniProt (SwissProt, PIR, EBI) http://www.pir.uniprot.org • NCBI Protein http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=Protein • More on these later: protein function prediction D Dobbs ISU - BCB 444/544X: Protein Structure Databases - cont.

  33. Protein sequence & structure: analysis • Diamond STING Millennium - many useful structure analysistools, includingProtein Dossierhttp://trantor.bioc.columbia.edu/SMS/ • SwissProt (UniProt) • protein knowledgebase • http://us.expasy.org/sprot • InterPRO • sequence analysis tools • http://www.ebi.ac.uk/interpro D Dobbs ISU - BCB 444/544X: Protein Structure Databases - cont.

  34. Protein structure databases • PDBProtein Data Bank http://www.rcsb.org/pdb/ • (RCSB) - THE protein structure database • MMDBMolecular Modeling Database • http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=Structure (NCBI Entrez) - has "added" value • MSD Molecular Structure Database http://www.ebi.ac.uk/msd Especially good for interactions, binding sites D Dobbs ISU - BCB 444/544X: Protein Structure Databases - cont.

  35. Protein structure classification • SCOP = Structural Classification of Proteins Levels reflect both evolutionary and structural relationships http://scop.mrc-lmb.cam.ac.uk/scop • CATH = Classification by Class, Architecture, Topology & Homology http://cathwww.biochem.ucl.ac.uk/latest/ • DALI/FSSP (recently moved to EBI & reorganized) • fully automated structure alignments • DALI server http://www.ebi.ac.uk/dali/index.html • DALI Database (fold classification) http://ekhidna.biocenter.helsinki.fi/dali/start D Dobbs ISU - BCB 444/544X: Protein Structure Databases - cont.

  36. Protein structure visualization • Molecular Visualization Freeware: • http://www.umass.edu/microbio/rasmol • MolviZ.Org • http://www.umass.edu/microbio/chime • Protein Explorer http://www.umass.edu/microbio/chime/pe/protexpl/frntdoor.htm • RASMOL (& many decendents: Protein Explorer,PyMol, MolMol, etc.) • http://www.umass.edu/microbio/rasmol/index2.htm • CHIME • http://www.umass.edu/microbio/chime/getchime.htm • Cn3Dhttp://www.biosino.org/mirror/www.ncbi.nlm.nih.gov/Structure/cn3d/ • Deep View = Swiss-PDB Viewer http://www.expasy.org/spdbv D Dobbs ISU - BCB 444/544X: Protein Structure Databases - cont.

  37. PDB (RCSB) http://www.rcsb.org/pdb D Dobbs ISU - BCB 444/544X: Protein Structure Databases - cont.

  38. RCSB PDB - Beta site http://pdbbeta.rcsb.org/pdb/Welcome.do D Dobbs ISU - BCB 444/544X: Protein Structure Databases - cont.

  39. RCSB PDB - New Tutorial http://core1.rcsb.org/tutorial D Dobbs ISU - BCB 444/544X: Protein Structure Databases - cont.

  40. NCBI Structurehttp://www.ncbi.nlm.nih.gov/Structure D Dobbs ISU - BCB 444/544X: Protein Structure Databases - cont.

  41. MMDBhttp://www.ncbi.nlm.nih.gov/Structure/MMDB/mmdb.shtml D Dobbs ISU - BCB 444/544X: Protein Structure Databases - cont.

  42. Cn3Dhttp://www.ncbi.nlm.nih.gov/Structure/CN3D/cn3d.shtml D Dobbs ISU - BCB 444/544X: Protein Structure Databases - cont.

  43. MMDB: Molecular Modeling Data Base • Derived PDB structure records • Value added to PDB records including: • Integration with other ENTREZ databases & tools • Conversion to parseable ASN.1 data description language • Correction of numbering discrepancies in structure vs sequence • Validation • Addition of explicit chemical graph information • Structure neighbors determined by Vector Alignment Search Tool (VAST) D Dobbs ISU - BCB 444/544X: Protein Structure Databases - cont.

  44. 1CET Searching MMDB D Dobbs ISU - BCB 444/544X: Protein Structure Databases - cont.

  45. MMDB Structure Summary BLAST neighbors VAST neighbors Cn3D viewer D Dobbs ISU - BCB 444/544X: Protein Structure Databases - cont.

  46. Cn3D : Displaying 2' Structures Chloroquine D Dobbs ISU - BCB 444/544X: Protein Structure Databases - cont.

  47. Cn3D : Displaying 3' Structures Chloroquine D Dobbs ISU - BCB 444/544X: Protein Structure Databases - cont.

  48. Cn3D: Structural Alignments Chloroquine NADH D Dobbs ISU - BCB 444/544X: Protein Structure Databases - cont.

  49. Protein Explorer (RasMol/Chime) D Dobbs ISU - BCB 444/544X: Protein Structure Databases - cont.

  50. Protein Explorer D Dobbs ISU - BCB 444/544X: Protein Structure Databases - cont.

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