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Using Sequence Information Into Protein Docking Procedure

Using Sequence Information Into Protein Docking Procedure. What did we want to do ?. Why did we want to do that ?. How did we want to do that ?. What did we want to do?. Incorporate sequence and experimental information into protein-protein or protein-ligand docking procedure

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Using Sequence Information Into Protein Docking Procedure

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  1. Using Sequence Information Into Protein Docking Procedure

  2. What did we want to do ? Why did we want to do that ? How did we want to do that ?

  3. What did we want to do? • Incorporate sequence and experimental information into protein-protein or protein-ligand docking procedure • Test the method by treating the case when two proteins are known to bind and 3D modells are available for both binding partners

  4. Why did we want to do that? Importance of protein-protein interaction in cellular processes We therefore need accurate tools to predict such events Methods exist with attempt to predict protein-protein docking Base on : • Shape complementarity (Shoichet & Kuntz, 1996; Janin et al., 1995) • Surface match (Helmer-Citterich &Tramontano, 1994; Walls & Sternberg, 1992) • Electrostatic (Gabdoulline & Wade, 1998; Vijayakumar et al., 1998) • Combination of some of the above strategy (Gabb et al., 1997)

  5. Improve existing methods Generate new approaches Sequence and structural data are actually on increase The need for combining sequence and structural information to: To predict protein-protein/ligand docking is urgent

  6. How did we want to do that? Define type of protein sequence to use Find out conserved residues in that protein family or subfamily Find out experimental and structural information available in the literatures Combine sequence and experimental Information to select residues to use to define distance constraints in the sdabf program (gabdoulline and Wade, 2002)

  7. Hope to make sampling more faster comparing to not using sequence and experimental information Hope to have correct docked structure and avoid false positives when sequence and experimental information are used

  8. WW domain alignment

  9. W11 F25 Y23 W34 The WW domain Definition: TheWW domainis a protein-protein interaction module compose of35-40 amino acids. It has3 anti-parallel beta-sheet, and isstablein the absence of disulfide bonds, cofactor or ligands P37

  10. The domain binds proline-rich or proline containing ligands it is evolutionary well conserved and present in plants, yeast, worm, fly and vertebrates

  11. Classification of WW domains Consensus sequence of the ligand Representative ligands Groups/representatives PEBP2 transcriptional activator, ENaC sodium channel, beta-dystroglycan PPxY PPPPPPL/RP Formin, Mena, Bat2 Splicing factors: SmB, SmB', U1C (PxxGMxPP)N Phospho-(S/T)P RNA Pol II, Cdc25C, p53 Rx(x)PPGPPPxR NpwBP http://www.bork.embl-heidelberg.de/Modules/ww_classes.html

  12. Function of the WW domain Variety of target Therefore involve in variety of cellular processes such as: - Co-activation of transcription and modulation of RNA pol II - Mitotic regulation (G2/M transition) - Protein processing … Implicate in several human diseases such as: - Muscular Dystrophy - Alzheimer’s disease - Hypertension - Cancer …

  13. Differences between the free and complexed pin1 WW domain

  14. PDB-file 1f8a Sequence alignment, experimental information Script „pdbExtractor“ file with coordinates of the WW-domain file with coordinates of the phosphorylated peptide remove phosphates coordinates of the dephosphorylated peptide Script„do_all_whatif“: add the H-atoms with “Whatif” dephosphorylated peptide +H-atoms +PO3- ; -HG of SER p1.pdb p2.pdb Script „do_bf_prepare”: UHBD, ECM, mk_ds_grid Script „rxnaEditor.py“ p1.rxna p2.rxna p1e.grd, p1.echa, p1ds.grd p2e.grd, p2.echa, p2ds.grd + other parameters (e.g. the distance constraint) sdabf12.in (input-file) Script „do-run“ start the simulation sdabfcw fort.xx* and other output-files Nmrclust, twopdb2rmsd.f, clusteranalyse.f Clustering and cluster analysis

  15. could sampling be speed up using sequence/experimental information?

  16. E12= Ecoul + Edes + Ehyd E12= Ecoul + Edes E12= Ecoul

  17. E12= Ecoul + Edes E12= Ecoul E12= Ecoul + Edes + Ehyd

  18. ComplexCen FreeCen Y27 Y23

  19. W38 Y27 W34 Y23

  20. *Independent distance = 6

  21. R21Y27W38 R17Y23W34 Grid sampling

  22. R21Y27W38 R17Y23W34 BD sampling

  23. Conclusion

  24. Thanks to All the MCM -GROUP members Special thanks to Rebecca Wade Razif Gabdoulline Jan Lac and Ting Wang

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