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BCB 444/544

BCB 444/544. Lecture 21 Protein Structure Visualization, Classification & Comparison Secondary Structure Prediction #21_Oct10. Required Reading ( before lecture). Mon Oct 8 - Lecture 20 Protein Secondary Structure Prediction Chp 14 - pp 200 - 213 Wed Oct 10 - Lecture 21

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BCB 444/544

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  1. BCB 444/544 Lecture 21 Protein Structure Visualization, Classification&Comparison • Secondary Structure Prediction #21_Oct10 BCB 444/544 F07 ISU Dobbs #21 - Protein Secondary Structure Prediction

  2. Required Reading (before lecture) MonOct 8- Lecture 20 Protein Secondary Structure Prediction • Chp 14 - pp 200 - 213 Wed Oct 10 - Lecture 21 Protein Tertiary Structure Prediction • Chp 15 - pp 214 - 230 Thurs Oct 11 & Fri Oct 12- Lab 7 & Lecture 22 Protein Tertiary Structure Prediction • Chp 15 - pp 214 - 230 BCB 444/544 F07 ISU Dobbs #21 - Protein Secondary Structure Prediction

  3. Assignments & Announcements ALL: HomeWork #3 √Due: Mon Oct 8 by 5 PM • HW544: HW544Extra #1 √Due: Task 1.1 - Mon Oct 1 by noon Due: Task 1.2 & Task 2 - Fri Oct 12 by 5 PM • 444 "Project-instead-of-Final" students should also submit: • HW544Extra #1 • √Due: Task 1.1 - Mon Oct 8 by noon • Due: Task 1.2 - Fri Oct 12 by 5 PM <Task 2 NOT required for BCB444 students> BCB 444/544 F07 ISU Dobbs #21 - Protein Secondary Structure Prediction

  4. Seminars this Week - Thurs: BCB List of URLs for Seminars related to Bioinformatics: http://www.bcb.iastate.edu/seminars/index.html • Oct 11 Thurs • Dr. Klaus Schulten (Univ of Illinois) - Baker Center Seminar The Computational Microscope2:10 PM in E164 Lagomarcinohttp://www.bioinformatics.iastate.edu/seminars/abstracts/2007_2008/Klaus_Schulten_Seminar.pdf • Dr. Dan Gusfield(UC Davis) - Computer Science ColloquiumReCombinatorics: Combinatorial Algorithms for Studying History of Recombination in Populations 3:30 PM in Howe Hall Auditorium http://www.cs.iastate.edu/~colloq/new/gusfield.shtml BCB 444/544 F07 ISU Dobbs #21 - Protein Secondary Structure Prediction

  5. Seminars this Week - Fri: BCB List of URLs for Seminars related to Bioinformatics: http://www.bcb.iastate.edu/seminars/index.html • Oct 12 Fri • Dr. Edward Yu(Physics/BBMB, ISU) - BCB Faculty Seminar TBA: "Structural Biology" (see URL below)2:10 PM in 102 Scihttp://webdev.its.iastate.edu/webnews/data/site_gdcb_dept_seminars/30/webnewsfilefield_abstract/Dr.-Ed-Yu.pdf • Dr. Srinivas Aluru (ECprE, ISU) - GDCB Seminar Consensus Genetic Maps: A Graph Theoretic Approach 4:10 PM in 1414 MBB http://webdev.its.iastate.edu/webnews/data/site_gdcb_dept_seminars/35/webnewsfilefield_abstract/Dr.-Srinivas-Aluru.pdf BCB 444/544 F07 ISU Dobbs #21 - Protein Secondary Structure Prediction

  6. Chp 12 - Protein Structure Basics SECTION V STRUCTURAL BIOINFORMATICS Xiong: Chp 12Protein Structure Basics • Amino Acids • Peptide Bond Formation • Dihedral Angles • Hierarchy • Secondary Structures • Tertiary Structures • Determination of Protein 3-Dimensional Structure • Protein Structure DataBank (PDB) BCB 444/544 F07 ISU Dobbs #21 - Protein Secondary Structure Prediction

  7. Protein Structure & Function • Protein structure - primarily determined by sequence • Protein function - primarily determined by structure • Globular proteins: compact hydrophobic core & hydrophilic surface • Membrane proteins: special hydrophobic surfaces • Folded proteins are only marginally stable • Some proteins do not assume a stable "fold" until they bind to something = Intrinsically disordered • Predicting protein structure and function can be very hard -- & fun! BCB 444/544 F07 ISU Dobbs #21 - Protein Secondary Structure Prediction

  8. 6 Main Classes of Protein Structure 1) a-Domains Bundles of helices connected by loops 2) -Domains Mainly antiparallel sheets, usually 2 sheets forming sandwich 3) aDomains Mainly parallel sheets with intervening helices, 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 BCB 444/544 F07 ISU Dobbs #21 - Protein Secondary Structure Prediction

  9. Protein Structure Databases PDB - Protein Data Bank http://www.rcsb.org/pdb/ (RCSB) - THE protein structure database MMDB - Molecular Modeling Database http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=Structure (NCBI Entrez) - has "added" value MSD - Molecular Structure Databasehttp://www.ebi.ac.uk/msd Especially good for interactions & binding sites BCB 444/544 F07 ISU Dobbs #21 - Protein Secondary Structure Prediction

  10. PDB (RCSB) - recently "remediated" http://www.rcsb.org/pdb BCB 444/544 F07 ISU Dobbs #21 - Protein Secondary Structure Prediction

  11. Structure at NCBIhttp://www.ncbi.nlm.nih.gov/Structure BCB 444/544 F07 ISU Dobbs #21 - Protein Secondary Structure Prediction

  12. MMDB at NCBIhttp://www.ncbi.nlm.nih.gov/Structure/MMDB/mmdb.shtml BCB 444/544 F07 ISU Dobbs #21 - Protein Secondary Structure Prediction

  13. MMDB: Molecular Modeling Data Base • Derived from PDB structure records • "Value-added" to PDB records includes: • Integration with other ENTREZ databases & tools • Conversion to parseable ASN.1 data description language • Data also available in mmCIF & XML (also true for PDB now) • Correction of numbering discrepancies in structure vs sequence • Validation • Explicit chemical graph information (covalent bonds) • Integrated tool for identifying structural neighbors Vector Alignment Search Tool (VAST) http://www.ncbi.nlm.nih.gov/Structure/VAST/vastsearch.html BCB 444/544 F07 ISU Dobbs #21 - Protein Secondary Structure Prediction

  14. MSD: Molecular StructureDatabasehttp://www.ebi.ac.uk/msd/ BCB 444/544 F07 ISU Dobbs #21 - Protein Secondary Structure Prediction

  15. wwPDB: World Wide PDBhttp://www.wwpdb.org BCB 444/544 F07 ISU Dobbs #21 - Protein Secondary Structure Prediction

  16. Experimental Determination of 3D Structure 2 Major Methods to obtain high-resolution structures • X-ray Crystallography(most PDB structures) • Nuclear Magnetic Resonance (NMR) Spectroscopy Note Advantages & Limitations of each method • (See your lecture notes & textbook) • For more info:http://en.wikipedia.org/wiki/Protein_structure • Other methods (usually lower resolution, at present): • Electron Paramagnetic Resonance (EPR - also called ESR, EMR) • Electron microscopy (EM) • Cryo-EM • Scanning Probe Microscopies (AFM - Atomic Force Microscopy) • http://www.uweb.engr.washington.edu/research/tutorials/SPM.pdf • Circular Dichroism (CD), several other spectroscopic methods BCB 444/544 F07 ISU Dobbs #21 - Protein Secondary Structure Prediction

  17. Chp 13 - Protein Structure Visualization, Comparison & Classification SECTION V STRUCTURAL BIOINFORMATICS Xiong: Chp 13 Protein Structure Visualization, Comparison & Classification • Protein Structural Visualization • Protein Structure Comparison • Protein Structure Classification BCB 444/544 F07 ISU Dobbs #21 - Protein Secondary Structure Prediction

  18. Protein Structure Visualization RASMOL & decendents: PyMol, MolMol http://www.umass.edu/microbio/rasmol/index2.htm Cn3D - esp. good for structural alignments http://www.biosino.org/mirror/www.ncbi.nlm.nih.gov/Structure/cn3d/ CHIME (Protein Explorer) http://www.umass.edu/microbio/chime/getchime.htm MolviZ.Org http://www.umass.edu/microbio/chime Deep View = Swiss-PDB Viewer http://www.expasy.org/spdbv BCB 444/544 F07 ISU Dobbs #21 - Protein Secondary Structure Prediction

  19. PyMolhttp://pymol.sourceforge.net/ BCB 444/544 F07 ISU Dobbs #21 - Protein Secondary Structure Prediction

  20. Cn3Dhttp://www.ncbi.nlm.nih.gov/Structure/CN3D/cn3d.shtml BCB 444/544 F07 ISU Dobbs #21 - Protein Secondary Structure Prediction

  21. Cn3D : Displaying 3' Structures Chloroquine BCB 444/544 F07 ISU Dobbs #21 - Protein Secondary Structure Prediction

  22. Cn3D: Structural Alignments NADH BCB 444/544 F07 ISU Dobbs #21 - Protein Secondary Structure Prediction

  23. Protein Explorer (Chime)http://www.umass.edu/microbio/chime/pe_beta/pe/protexpl/frntdoor.htm BCB 444/544 F07 ISU Dobbs #21 - Protein Secondary Structure Prediction

  24. Protein Structure Comparison Methods We will skip this for now 3 Basic Approaches for Aligning Structures: • Intermolecular - • Intramolecular - • Combined - • DALI/FSSP (most commonly used) Fully automated structure alignments • DALI serverhttp://www.ebi.ac.uk/dali/index.html • DALI Database (fold classification) http://ekhidna.biocenter.helsinki.fi/dali/start BCB 444/544 F07 ISU Dobbs #21 - Protein Secondary Structure Prediction

  25. 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 & Homologyhttp://cathwww.biochem.ucl.ac.uk/latest/ • DALI -(recently moved to EBI & reorganized) DALI Database (fold classification)http://ekhidna.biocenter.helsinki.fi/dali/start Each method has strengths & weaknesses…. BCB 444/544 F07 ISU Dobbs #21 - Protein Secondary Structure Prediction

  26. SCOP - Structure Classificationhttp://scop.mrc-lmb.cam.ac.uk/scop/ BCB 444/544 F07 ISU Dobbs #21 - Protein Secondary Structure Prediction

  27. CATH - Structure Classificationhttp://www.cathdb.info/latest/index.html BCB 444/544 F07 ISU Dobbs #21 - Protein Secondary Structure Prediction

  28. Chp 14 - Secondary Structure Prediction SECTION V STRUCTURAL BIOINFORMATICS Xiong: Chp 14 Protein Secondary Structure Prediction • Secondary Structure Prediction for Globular Proteins • Secondary Structure Prediction for Transmembrane Proteins • Coiled-Coil Prediction BCB 444/544 F07 ISU Dobbs #21 - Protein Secondary Structure Prediction

  29. Secondary Structure Prediction Has become highly accurate in recent years (>85%) • Usually 3 (or 4) state predictions: • H = -helix • E = -strand • C = coil (or loop) • (T = turn) BCB 444/544 F07 ISU Dobbs #21 - Protein Secondary Structure Prediction

  30. Secondary Structure Prediction Methods • 1st Generation methods Ab initio - used relatively small dataset of structures available Chou-Fasman - based on amino acid propensities (3-state) GOR - also propensity-based (4-state) • 2nd Generation methods based on much larger datasets of structures now available GOR II, III, IV, SOPM • 3rd Generation methods Homology-based & Neural network based PHD, PSIPRED, SSPRO, PROF, HMMSTR • Meta-Servers combine several different methods Consensus & Ensemble based JPRED, PredictProtein BCB 444/544 F07 ISU Dobbs #21 - Protein Secondary Structure Prediction

  31. Secondary Structure Prediction Servers Prediction Evaluation? • Q3 score - % of residues correctly predicted (3-state) in cross-validation experiments Best results? Meta-servers • http://expasy.org/tools/(scroll for 2' structure prediction) • http://www.russell.embl-heidelberg.de/gtsp/secstrucpred.html • JPred www.compbio.dundee.ac.uk/~www-jpred • PredictProteinhttp://www.predictprotein.org/Rost, Columbia Best individual programs? ?? • CDM http://gor.bb.iastate.edu/cdm/ Sen…Jernigan, ISU • GOR Vhttp://gor.bb.iastate.edu/ Kloczkowsky…Jernigan, ISU BCB 444/544 F07 ISU Dobbs #21 - Protein Secondary Structure Prediction

  32. Consensus Data Mining (CDM) • Developed by Jernigan Group at ISU • Basic premise: combination of 2 complementary methods can enhance performance by harnessing distinct advantages of both methods; combines FDM & GOR V: • FDM - Fragment Data Mining - exploits availability of sequence-similar fragments in the PDB, which can lead to highly accurate prediction - much better than GOR V - for such fragments, but such fragments are not available for many cases • GOR V - Garnier, Osguthorpe, Robson V - predicts secondary structure of less similar fragments with good performance; these are protein fragments for which FDM method cannot find suitable structures • For references & additional details: http://gor.bb.iastate.edu/cdm/ BCB 444/544 F07 ISU Dobbs #21 - Protein Secondary Structure Prediction

  33. Secondary Structure Prediction: for Different Types of Proteins/Domains For Complete proteins: Globular Proteins - use methods previously described Transmembrane (TMM) Proteins - use special methods (next slides) For Structural Domains:many under development: Coiled-Coil Domains (Protein interaction domains) Zinc Finger Domains (DNA binding domains), others… BCB 444/544 F07 ISU Dobbs #21 - Protein Secondary Structure Prediction

  34. SS Prediction for Transmembrane Proteins Transmembrane (TM) Proteins • Only a few in the PDB - but ~ 30% of cellular proteins are membrane-associated ! • Hard to determine experimentally, so prediction important • TM domains are relatively 'easy' to predict! Why? constraints due to hydrophobic environment 2 main classes of TM proteins: -helical - barrel BCB 444/544 F07 ISU Dobbs #21 - Protein Secondary Structure Prediction

  35. SS Prediction for TM -Helices -Helical TM domains: • Helices are 17-25 amino acids long (span the membrane) • Predominantly hydrophobic residues • Helices oriented perpendicular to membrane • Orientation can be predicted using "positive inside" rule Residues at cytosolic(inside or cytoplasmic) side of TM helix, near hydrophobic anchor are more positively charged than those on lumenal (inside an organelle in eukaryotes) or periplasmicside (space between inner & outer membrane in gram-negative bacteria) • Alternating polar & hydrophobic residues provide clues to interactions among helices within membrane Servers? • TMHMM or HMMTOP - 70% accuracy - confused by hydrophobic signal peptides (short hydrophobic sequences that target proteins to the endoplasmic reticulum, ER) • Phobius - 94% accuracy - uses distinct HMM models for TM helices & signal peptide sequences BCB 444/544 F07 ISU Dobbs #21 - Protein Secondary Structure Prediction

  36. SS Prediction for TM -Barrels -Barrel TM domains:  • -strands are amphipathic (partly hydrophobic, partly hydrophilic) • Strands are 10 - 22 amino acids long • Every 2nd residue is hydrophobic, facing lipid bilayer • Other residues are hydrophilic, facing "pore" or opening Servers?Harder problem, fewer servers… TBBPred - uses NN or SVM (more on these ML methods later) Accuracy ? BCB 444/544 F07 ISU Dobbs #21 - Protein Secondary Structure Prediction

  37. Prediction of Coiled-Coil Domains Coiled-coils • Superhelical protein motifs or domains, with two or more interacting -helices that form a "bundle" • Often mediate inter-protein (& intra-protein) interactions 'Easy' to detect in primary sequence: • Internal repeat of 7 residues (heptad) • 1 & 4 = hydrophobic (facing helical interface) • 2,3,5,6,7 = hydrophilic (exposed to solvent) • Helical wheel representation - can be used manually detect these, based on amino acid sequence Servers? Coils, Multicoil -probability-based methods 2Zip - for Leucine zippers = special type of CC in TFs: characterized by Leu-rich motif: L-X(6)-L-X(6)-L-X(6)-L BCB 444/544 F07 ISU Dobbs #21 - Protein Secondary Structure Prediction

  38. Chp 15 - Tertiary Structure Prediction SECTION V STRUCTURAL BIOINFORMATICS Xiong: Chp 15 Protein Tertiary Structure Prediction • Methods • Homology Modeling • Threading and Fold Recognition • Ab Initio Protein Structural Prediction • CASP BCB 444/544 F07 ISU Dobbs #21 - Protein Secondary Structure Prediction

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