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Protein Docking

Enhance protein docking efficiency with FFT rotational sampling, shape complementarity, and energy optimization for successful molecular complex predictions.

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Protein Docking

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  1. Protein Docking Rong Chen Boston University

  2. L L L L R R L R R R The Lowest Binding Free Energy DG water

  3. R Fast Fourier Transform R Discretize Complex Conjugate R Correlation function L Rotate Discretize L L Fast Fourier Transform Surface Interior Protein Docking Using FFT

  4. Rotational Sampling • Evenly distributed Euler angles

  5. Performance Evaluation • Success Rate: given the number of predictions(Np), success rate is the percentage of complexes in the benchmark for which at least one hit has been obtained. • Hit Count: the average number of hits over all complexes at a particular Np.

  6. Rotational Sampling Density

  7. Rotational Sampling Density

  8. R Fast Fourier Transform R Discretize Complex Conjugate R Correlation function L Rotate Discretize L L Fast Fourier Transform Surface Interior Protein Docking Using FFT

  9. R IFFT Correlation L Y Translation X Translation Surface Interior Binding Site Protein Docking Using FFT Increase the speed by 107

  10. van der Waals energy; Shape complementarity Desolvation energy; Hydrophobicity Electrostatic interaction energy Translational, rotational and vibrational free energy changes An Effective Binding Free Energy Function Number of atom pairs of type i Desolvation energy for an atom pair of type i

  11. 1 1 1 1 1 1 1 9i 9i 9i 9i 9i 1 9i 9i 9i 9i 9i 1 1 1 1 1 1 9i 9i 9i 9i 1 1 9i 1 1 9i 9i 9i 1 1 1 1 9i 9i 1 9i 9i 9i 9i 9i 1 1 1 1 9i 9i 9i 9i 9i 1 1 1 1 1 1 1 RGSC LGSC Grid-based Shape Complementarity

  12. 1 1 2 3 3 3 2 2 2 3i 3i 3i 3i 3i 3 3i 9i 3i 3i 3i 2 1+3i 1+3i 3 5 2 3i 9i 3i 1 1+9i 1+3i 1+3i 1+9i 1+3i 3 3i 9i 3i 5 2 1 1+3i 1+3i 1+9i 1+9i 1+3i 3i 9i 3i 3i 3i 3 2 1+3i 1+3i 3i 3i 3i 3i 3i 2 2 2 3 3 3 2 1 1 RPSC LPSC PairwiseShape Complementarity

  13. PSC vs. GSC on Success Rate

  14. PSC vs. GSC on Hit Count

  15. Why PSC works better than GSC?

  16. A C B D Why PSC works better than GSC?

  17. A Receptor-Ligand Complex

  18. van der Waals energy; Shape complementarity Desolvation energy; Hydrophobicity Electrostatic interaction energy Translational, rotational and vibrational free energy changes An Effective Binding Free Energy Function Number of atom pairs of type i-j Desolvation energy for an atom pair of type i-j

  19. Impact of Desolvation and Electrostatics

  20. Impact of Desolvation and Electrostatics

  21. Other available Docking Software • Fast Fourier Transform or FFT (Katchalski-Katzir, Sternberg, Vakser, Ten Eyck groups) • Computer vision based method (Nussinov group, 1999) • Boolean operations (Palma et al., 2000) • Polar Fourier correlations (Ritchie & Kemp, 2000) • Genetic algorithm (Gardiner, Burnett groups) • Flexible docking (Abagyan, 2002)

  22. 3D-Dock • Michael J.E. Sternberg, Imperial Cancer Research Fund, London, UK. • FTDock: Grid-based shape complementarity, FFT. • RPScore: empirical pair potential. • MultiDock: refinement. • http://www.bmm.icnet.uk/docking/index.html

  23. GRAMM • Ilya A. Vakser, State University of New York at Stony Brook. • Geometric fit and hydrophobicity • FFT • Low resolution docking • http://reco3.ams.sunysb.edu/gramm/

  24. DOT • Lynn F. Ten Eyck, University of California, San Diego. • Grid-based shape complemetarity, elctrostatics • FFT • http://www.sdsc.edu/CCMS/Papers/DOT_sc95.html

  25. ICM • Ruben Abagyan, The Scripps Research Institute, La Jolla. • Pseudo-Brownian rigid-body docking • Biased Probability Monte Carlo Minimization of the ligand interacting side-chains. • http://abagyan.scripps.edu/lab/web/man/frames.htm

  26. HEX • Dave Ritchie, University of Aberdeen, Aberdeen, Scotland, UK • spherical polar Fourier correlations • http://www.biochem.abdn.ac.uk/hex/

  27. Approach Overview PDB2 PDB1 PDB Processing ZDOCK: Initial-stage Docking Biological information RDOCK: Refinement-stage Docking Clustering Final 10 predictions

  28. Example: • CAPRI Target 6: α-amylase / Camelid VHH domain

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