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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 l.jpg
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


Required reading before lecture l.jpg
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


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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


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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


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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


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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


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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


6 main classes of protein structure l.jpg
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


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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


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PDB (RCSB) - recently "remediated" http://www.rcsb.org/pdb

BCB 444/544 F07 ISU Dobbs #21 - Protein Secondary Structure Prediction


Structure at ncbi http www ncbi nlm nih gov structure l.jpg
Structure at NCBIhttp://www.ncbi.nlm.nih.gov/Structure

BCB 444/544 F07 ISU Dobbs #21 - Protein Secondary Structure Prediction


Mmdb at ncbi http www ncbi nlm nih gov structure mmdb mmdb shtml l.jpg
MMDB at NCBIhttp://www.ncbi.nlm.nih.gov/Structure/MMDB/mmdb.shtml

BCB 444/544 F07 ISU Dobbs #21 - Protein Secondary Structure Prediction


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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


Msd m olecular s tructure d atabase http www ebi ac uk msd l.jpg
MSD: Molecular StructureDatabasehttp://www.ebi.ac.uk/msd/

BCB 444/544 F07 ISU Dobbs #21 - Protein Secondary Structure Prediction


Wwpdb world wide pdb http www wwpdb org l.jpg
wwPDB: World Wide PDBhttp://www.wwpdb.org

BCB 444/544 F07 ISU Dobbs #21 - Protein Secondary Structure Prediction


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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


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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


Protein structure visualization l.jpg
Protein Structure Visualization Classification

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


Pymol http pymol sourceforge net l.jpg
PyMol Classificationhttp://pymol.sourceforge.net/

BCB 444/544 F07 ISU Dobbs #21 - Protein Secondary Structure Prediction


Cn3d http www ncbi nlm nih gov structure cn3d cn3d shtml l.jpg
Cn3D Classificationhttp://www.ncbi.nlm.nih.gov/Structure/CN3D/cn3d.shtml

BCB 444/544 F07 ISU Dobbs #21 - Protein Secondary Structure Prediction


Cn3d displaying 3 structures l.jpg
Cn3D : Displaying 3' Structures Classification

Chloroquine

BCB 444/544 F07 ISU Dobbs #21 - Protein Secondary Structure Prediction


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Cn3D: Structural Alignments Classification

NADH

BCB 444/544 F07 ISU Dobbs #21 - Protein Secondary Structure Prediction


Protein explorer chime http www umass edu microbio chime pe beta pe protexpl frntdoor htm l.jpg
Protein Explorer (Chime) Classificationhttp://www.umass.edu/microbio/chime/pe_beta/pe/protexpl/frntdoor.htm

BCB 444/544 F07 ISU Dobbs #21 - Protein Secondary Structure Prediction


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Protein Structure Comparison Methods Classification

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


    Protein structure classification l.jpg
    Protein Structure Classification 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


    Scop structure classification http scop mrc lmb cam ac uk scop l.jpg
    SCOP - Structure Classification Classificationhttp://scop.mrc-lmb.cam.ac.uk/scop/

    BCB 444/544 F07 ISU Dobbs #21 - Protein Secondary Structure Prediction


    Cath structure classification http www cathdb info latest index html l.jpg
    CATH - Structure Classification Classificationhttp://www.cathdb.info/latest/index.html

    BCB 444/544 F07 ISU Dobbs #21 - Protein Secondary Structure Prediction


    Chp 14 secondary structure prediction l.jpg
    Chp 14 - Secondary Structure Prediction Classification

    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


    Secondary structure prediction l.jpg
    Secondary Structure Prediction Classification

    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


    Secondary structure prediction methods l.jpg
    Secondary Structure Prediction Methods Classification

    • 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


    Secondary structure prediction servers l.jpg
    Secondary Structure Prediction Servers Classification

    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


    Consensus data mining cdm l.jpg
    Consensus Data Mining (CDM) Classification

    • 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


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    Secondary Structure Prediction: Classificationfor 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


    Ss prediction for transmembrane proteins l.jpg
    SS Prediction for Transmembrane Proteins Classification

    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


    Ss prediction for tm helices l.jpg
    SS Prediction for TM Classification-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


    Ss prediction for tm barrels l.jpg
    SS Prediction for TM Classification-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


    Prediction of coiled coil domains l.jpg
    Prediction of Coiled-Coil Domains Classification

    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


    Chp 15 tertiary structure prediction l.jpg
    Chp 15 - Tertiary Structure Prediction Classification

    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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