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Practical session 2b Introduction to 3D Modelling and threading 9:30am-10:00am

Practical session 2b Introduction to 3D Modelling and threading 9:30am-10:00am 3D modeling and threading 10:00am-10:30am Analysis of mutations in MYH6. Miguel Andrade Max Delbr ück Center for Molecular Medicine Miguel.andrade @ mdc-berlin.de. Introduction. Protein tertiary structure.

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Practical session 2b Introduction to 3D Modelling and threading 9:30am-10:00am

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  1. Practical session 2b Introduction to 3D Modelling and threading 9:30am-10:00am 3D modeling and threading 10:00am-10:30am Analysis of mutations in MYH6 Miguel Andrade Max Delbrück Center for Molecular Medicine Miguel.andrade@mdc-berlin.de

  2. Introduction Protein tertiary structure Secondary structure elements fold together

  3. Introduction Protein quaternary structure Folded proteins form a complex

  4. Introduction Protein domains are structural units (average 160 aa) that share: Function Folding Evolution Proteins normally are multidomain (average 300 aa)

  5. Introduction Protein domains are structural units (average 160 aa) that share: Function Folding Evolution Proteins normally are multidomain (average 300 aa)

  6. Determination of protein structure X-ray crystallography (70,714 in PDB) • need crystals Nuclear Magnetic Resonance (NMR) (9,312) • proteins in solution • lower size limit (600 aa) Electron microscopy (422) • Low resolution (>5A)

  7. Determination of protein structure resolution 2.4 A

  8. Determination of protein structure resolution 2.4 A

  9. Structural genomics Currently: 81K 3D structures from around 27K seqs 16M sequences in UniProt only 0.17%!

  10. Structural genomics Currently: 81K 3D structures from around 27K seqs 16M sequences in UniProt only 0.17%! 50% sequences covered (25% in 1995)

  11. Strategy for analysis Predict domains Cut Similar to PDB sequence? No 2D Prediction 3D Ab initio 3D Threading Yes 3D Modeling by homology Query Sequence

  12. 3D structure prediction Approaches Class 1 Threading Comparative modeling Need similarity to a known structure Class 2 Ab initio Need sequence only

  13. 3D structure prediction Approaches Comparative modeling (30% to 50% id) Search for sequences of known structure similar to target Model from template core regions and from loops and side chains of structures that might be unrelated Atom coordinates from conserved residues Optimize distance constraints derived from sequence-template alignment Extra methods for loops, turns, and side chains

  14. 3D structure prediction Approaches Threading (identity can be lower than 30%) Thread target sequence through a library of known folds. Select right fold based on energy considerations More computational cost – but detect more distant relationships

  15. 3D structure prediction Approaches Ab initio Explore conformational space Limit the number of atoms Break the problem into fragments of sequence Optimize hydrophobic residue burial and pairing of beta-strands Limited success

  16. Relation between sequence identity and accuracy/applications From: Baker and Sali (2001) Science

  17. 3D structure prediction similar to L G + Leu Lys Gly Gly catalytic center known 3D model 3D by homology Applications: target design Query sequence G K

  18. 3D structure prediction Applications: fit to low res 3D Query sequence 1 Query sequence 2 low resolution 3D (electron microscopy)

  19. 3D structure prediction GenTHREADER David Jones http://bioinf.cs.ucl.ac.uk/psipred/ Input sequence Relatively quick, 5 minutes GenTHREADER Jones (1999) J Mol Biol

  20. 3D structure prediction GenTHREADER Output GenTHREADER

  21. 3D structure prediction Phyre http://www.sbg.bio.ic.ac.uk/phyre2/ Kelley et al (2000) J Mol Biol Kelley and Sternberg (2009) Nature Protocols

  22. 3D structure prediction I-Tasser Jeffrey Skolnick Tasser Yang Zhang I-Tasser Threading Fold 66% sequences <200 aa long of low homology to PDB Just submit your sequence and wait… (some days) Output are predicted structures (PDB format) Lee and Skolnick (2008) Biophysical Journal Roy et al (2010) Nature Methods

  23. 3D structure prediction I-Tasser Roy et al (2010) Nature Methods

  24. 3D structure prediction I-Tasser http://zhanglab.ccmb.med.umich.edu/I-TASSER/

  25. 3D structure prediction I-Tasser

  26. 3D structure prediction QUARK http://zhanglab.ccmb.med.umich.edu/QUARK/

  27. 3D structure prediction MODbase Andrej Sali http://modbase.compbio.ucsf.edu/ Pieper et al (2011) Nucleic Acids Research

  28. 3D structure prediction MODbase

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