11 9 05 protein structure databases continued prediction modeling
Download
1 / 58

11/9/05 Protein Structure Databases (continued) Prediction & Modeling - PowerPoint PPT Presentation


  • 294 Views
  • Uploaded on

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

loader
I am the owner, or an agent authorized to act on behalf of the owner, of the copyrighted work described.
capcha
Download Presentation

PowerPoint Slideshow about ' 11/9/05 Protein Structure Databases (continued) Prediction & Modeling ' - KeelyKia


An Image/Link below is provided (as is) to download presentation

Download Policy: Content on the Website is provided to you AS IS for your information and personal use and may not be sold / licensed / shared on other websites without getting consent from its author.While downloading, if for some reason you are not able to download a presentation, the publisher may have deleted the file from their server.


- - - - - - - - - - - - - - - - - - - - - - - - - - E N D - - - - - - - - - - - - - - - - - - - - - - - - - -
Presentation Transcript
11 9 05 protein structure databases continued prediction modeling l.jpg
11/9/05Protein Structure Databases (continued) Prediction & Modeling

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


Bioinformatics seminars l.jpg
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 l.jpg
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 l.jpg

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 l.jpg
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 l.jpg
Review last lecture:Protein Structure: Basics

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


Protein structure function l.jpg
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 l.jpg
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 l.jpg
Peptide bond is rigid and planar

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


Hydrophobic amino acids l.jpg
Hydrophobic Amino Acids

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


Charged amino acids l.jpg
Charged Amino Acids

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


Polar amino acids l.jpg
Polar Amino Acids

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


Certain side chain configurations are energetically favored rotamers l.jpg
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 l.jpg
Glycine is smallest amino acid (rotamers) R 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 l.jpg
Proline is cyclic (rotamers)

  • 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 l.jpg
Cysteines can form disulfide bonds (rotamers)

  • 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 l.jpg
Globular proteins have a compact hydrophobic core (rotamers)

  • 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 l.jpg
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 l.jpg
Protein Secondary Structures hydrophilic

  • 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 l.jpg
 hydrophilichelix: 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 l.jpg
Certain amino acids are "preferred" & others are rare in hydrophilic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 l.jpg
hydrophilic-sheets - also stabilized by H-bonds between back bone atoms

Anti-parallel

Parallel

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


Loops l.jpg
hydrophilicLoops

  • 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 l.jpg
Coils hydrophilic

  • 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 l.jpg
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 l.jpg
Simple motifs combine to form domains patterns

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


6 main classes of protein structure l.jpg
6 main classes of protein structure patterns

  • 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 l.jpg
    patterns-domain structures: 4-helix bundles

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


    Sheets up and down sheets barrels l.jpg
    patterns-sheets: up-and-down sheets & barrels

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


    A domains leucine rich motifs can form horseshoes l.jpg
    a patterns-domains: leucine-rich motifs can form horseshoes

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


    Slide31 l.jpg

    New today: patternsProtein Structure

    Databases

    ClassificationVisualization

    Protein Structure Prediction

    Secondary structure Tertiary structure

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


    Protein sequence databases l.jpg
    Protein sequence databases patterns

    • 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 l.jpg
    Protein sequence & structure: analysis patterns

    • 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 l.jpg
    Protein structure databases patterns

    • 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 l.jpg
    Protein structure classification patterns

    • 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 l.jpg
    Protein structure visualization patterns

    • 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 l.jpg
    PDB (RCSB) patternshttp://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 l.jpg
    RCSB PDB - Beta site patternshttp://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 l.jpg
    RCSB PDB - New Tutorial patternshttp://core1.rcsb.org/tutorial

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


    Ncbi structure http www ncbi nlm nih gov structure l.jpg
    NCBI Structure patternshttp://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 l.jpg
    MMDB patternshttp://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 l.jpg
    Cn3D patternshttp://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 l.jpg
    MMDB: patternsMolecular 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 l.jpg

    1CET patterns

    Searching MMDB

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


    Mmdb structure summary l.jpg
    MMDB Structure Summary patterns

    BLAST neighbors

    VAST neighbors

    Cn3D viewer

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


    Cn3d displaying 2 structures l.jpg
    Cn3D : Displaying 2' Structures patterns

    Chloroquine

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


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

    Chloroquine

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


    Cn3d structural alignments l.jpg
    Cn3D: Structural Alignments patterns

    Chloroquine

    NADH

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


    Protein explorer rasmol chime l.jpg
    Protein Explorer (RasMol/Chime) patterns

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


    Protein explorer l.jpg
    Protein Explorer patterns

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


    Scop structure classification l.jpg
    SCOP - Structure Classification patterns

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


    Cath structure classification l.jpg
    CATH - Structure Classification patterns

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


    Structural genomics l.jpg
    Structural Genomics patterns

    • ~ 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 l.jpg
    Structural Genomics Projects patterns

    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 l.jpg
    Protein Folding patterns

    • "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 l.jpg
    Steps in Protein Folding patterns

    • 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 l.jpg
    Protein Dynamics patterns

    • 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 l.jpg
    Protein Structure Prediction patterns

    • 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.


    ad