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

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

bioinformatics seminars
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.

bioinformatics seminars3
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.

protein structure function analysis prediction

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.

reading assignment for mon fri
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.

review last lecture protein structure basics
Review last lecture:Protein Structure: Basics

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

protein structure function
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.

amino acids
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.

peptide bond is rigid and planar
Peptide bond is rigid and planar

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

hydrophobic amino acids
Hydrophobic Amino Acids

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

charged amino acids
Charged Amino Acids

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

polar amino acids
Polar Amino Acids

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

certain side chain configurations are energetically favored rotamers
Certain side-chain configurations are energetically favored (rotamers)

Ramachandran plot:

"Allowable" psi & phi angles

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

glycine is smallest amino acid r group h atom
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.

proline is cyclic
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.

cysteines can form disulfide bonds
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.

globular proteins have a compact hydrophobic core
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.

exterior surface of globular proteins is generally hydrophilic
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.

protein secondary structures
Protein Secondary Structures
  • Helices
  • Sheets
  • Loops
  • Coils

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

helix stabilized by h bonds between every 4th residue in backbone
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.

certain amino acids are preferred others are rare in helices
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.

sheets also stabilized by h bonds between back bone atoms
-sheets - also stabilized by H-bonds between back bone atoms

Anti-parallel

Parallel

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

loops
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.

coils
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.

globular proteins are built from recurring structural patterns
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.

simple motifs combine to form domains
Simple motifs combine to form domains

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

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 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.

domain structures 4 helix bundles
-domain structures: 4-helix bundles

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

sheets up and down sheets barrels
-sheets: up-and-down sheets & barrels

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

a domains leucine rich motifs can form horseshoes
a-domains: leucine-rich motifs can form horseshoes

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

slide31
New today:Protein Structure

Databases

ClassificationVisualization

Protein Structure Prediction

Secondary structure Tertiary structure

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

protein sequence databases
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.

protein sequence structure analysis
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.

protein structure databases
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.

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 & 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.

protein structure visualization
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.

pdb rcsb http www rcsb org pdb
PDB (RCSB) http://www.rcsb.org/pdb

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

rcsb pdb beta site http pdbbeta rcsb org pdb welcome do
RCSB PDB - Beta site http://pdbbeta.rcsb.org/pdb/Welcome.do

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

rcsb pdb new tutorial http core1 rcsb org tutorial
RCSB PDB - New Tutorial http://core1.rcsb.org/tutorial

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

ncbi structure http www ncbi nlm nih gov structure
NCBI Structurehttp://www.ncbi.nlm.nih.gov/Structure

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

mmdb http www ncbi nlm nih gov structure mmdb mmdb shtml
MMDBhttp://www.ncbi.nlm.nih.gov/Structure/MMDB/mmdb.shtml

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

cn3d http www ncbi nlm nih gov structure cn3d cn3d shtml
Cn3Dhttp://www.ncbi.nlm.nih.gov/Structure/CN3D/cn3d.shtml

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

mmdb m olecular m odeling d ata b ase
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.

searching mmdb
1CETSearching MMDB

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

mmdb structure summary
MMDB Structure Summary

BLAST neighbors

VAST neighbors

Cn3D viewer

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

cn3d displaying 2 structures
Cn3D : Displaying 2' Structures

Chloroquine

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

cn3d displaying 3 structures
Cn3D : Displaying 3' Structures

Chloroquine

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

cn3d structural alignments
Cn3D: Structural Alignments

Chloroquine

NADH

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

protein explorer rasmol chime
Protein Explorer (RasMol/Chime)

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

protein explorer
Protein Explorer

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

scop structure classification
SCOP - Structure Classification

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

cath structure classification
CATH - Structure Classification

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

structural genomics
Structural Genomics
  • ~ 30,000 "traditional" genes in human genome
  • (not counting: ???)

~ 3,000 proteins in a typical cell

> 2 million sequences in UniProt

> 33,000 protein structures in the PDB

    • Experimental determination of protein structure lags far behind sequence determination!

Goal: Determine structures of "all" protein folds in nature, using combination of experimental structure determination methods (X-ray crystallography, NMR, mass spectrometry) & structure prediction

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

structural genomics projects
Structural Genomics Projects

TargetDB: database of structural genomics targets

http://targetdb.pdb.org

Protein Structure Prediction?

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

protein folding
Protein Folding
  • "Major unsolved problem in molecular biology"
  • In cells: spontaneous
  • assisted by enzymes
  • assisted by chaperones
  • In vitro: many proteins fold spontaneously
  • & many do not!

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

steps in protein folding
Steps in Protein Folding
  • 1- "Collapse"- driving force is burial of hydrophobic aa’s
  • (fast - msecs)
  • 2- Molten globule - helices & sheets form, but "loose"
  • (slow - secs)
  • 3- "Final" native folded state - compaction, some 2' structures rearranged
  • Native state? - assumed to be lowest free energy
  • - may be an ensemble of structures

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

protein dynamics
Protein Dynamics
  • Protein in native state is NOT static
  • Function of many proteins depends on conformational changes, sometimes large, sometimes small
  • Globular proteins are inherently "unstable"
  • (NOT evolved for maximum stability)
  • Energy difference between native and denatured state is very small (5-15 kcal/mol)
  • (this is equivalent to 1 or 2 H-bonds!)
  • Folding involves changes in both entropy & enthalpy

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

protein structure prediction
Protein Structure Prediction
  • Structure is largely determined by sequence

BUT:

    • Similar sequences can assume different structures
    • Dissimilar sequences can assume similar structures
    • Many proteins are multi-functional
    • Protein folding:
      • determination of folding pathways
      • prediction of tertiary structure
        • still largely unsolved problems

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

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