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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
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
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

assignments announcements
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

seminars this week thurs
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

seminars this week fri
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

chp 12 protein structure basics
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

protein structure function
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
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

protein structure databases
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

pdb rcsb recently remediated http www rcsb org pdb
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
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
MMDB at NCBIhttp://www.ncbi.nlm.nih.gov/Structure/MMDB/mmdb.shtml

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

mmdb m olecular m odeling d ata b ase
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
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
wwPDB: World Wide PDBhttp://www.wwpdb.org

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

experimental determination of 3d structure
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

chp 13 protein structure visualization comparison classification
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
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

pymol http pymol sourceforge net
PyMolhttp://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
Cn3Dhttp://www.ncbi.nlm.nih.gov/Structure/CN3D/cn3d.shtml

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

cn3d displaying 3 structures
Cn3D : Displaying 3' Structures

Chloroquine

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

cn3d structural alignments
Cn3D: Structural Alignments

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
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

protein structure comparison methods
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

protein structure classification
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

scop structure classification http scop mrc lmb cam ac uk scop
SCOP - Structure 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
CATH - Structure Classificationhttp://www.cathdb.info/latest/index.html

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

chp 14 secondary structure prediction
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

secondary structure prediction
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

secondary structure prediction methods
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

secondary structure prediction servers
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

consensus data mining cdm
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

secondary structure prediction for different types of proteins domains
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

ss prediction for transmembrane proteins
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

ss prediction for tm helices
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

ss prediction for tm barrels
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

prediction of coiled coil domains
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

chp 15 tertiary structure prediction
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