1. Protein Docking Rong Chen Boston University

2. BU Bioinformatics The Lowest Binding Free Energy  G water R L R L L R L R L R

3. BU Bioinformatics Protein Docking Using FFT R L L R R L Rotate Fast Fourier Transform Complex Conjugate Discretize Fast Fourier Transform SurfaceInterior Correlation function

4. BU Bioinformatics Rotational Sampling Evenly distributed Euler angles Sampling IntervalNumber of angles 20°1,800 15°3,600 12°9,000 10°14,400 8°27,000 6°54,000 4°180,000

5. BU Bioinformatics Performance Evaluation Success Rate: given the number of predictions(N p ), 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 N p.

6. BU Bioinformatics Rotational Sampling Density

7. BU Bioinformatics Rotational Sampling Density

8. BU Bioinformatics Protein Docking Using FFT R L L R R L Rotate Fast Fourier Transform Complex Conjugate Discretize Fast Fourier Transform SurfaceInterior Correlation function

9. BU Bioinformatics Protein Docking Using FFT SurfaceInteriorBinding Site Y Translation Correlation X Translation IFFT Increase the speed by 10 7

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

11. BU Bioinformatics 9i9i9i9i9i9i9i9i9i9i 9i9i9i9i9i9i9i9i9i9i 9i9i9i9i9i9i 9i9i9i9i9i9i 9i9i9i9i9i9i9i9i9i9i 9i9i9i9i9i9i9i9i9i9i 11 11111 11 111 111 11 11 11111 1 119i9i 119i9i9i9i1 11 1 9i9i 1 R GSC L GSC Grid-based Shape Complementarity

12. BU Bioinformatics R PSC L PSC 1+3i 1+9i 1+3i 1+9i 1+3i 1+9i 1+3i 3i3i3i3i3i3i3i3i3i3i 3i3i9i9i3i3i3i3i3i3i 3i3i9i9i3i3i 3i3i9i9i3i3i 3i3i9i9i3i3i3i3i3i3i 3i3i3i3i3i3i3i3i3i3i 22 33232 23 523 523 23 22 33232 1 1 1 11 1 Pairwise Shape Complementarity

13. BU Bioinformatics PSC vs. GSC on Success Rate

14. BU Bioinformatics PSC vs. GSC on Hit Count

15. BU Bioinformatics Why PSC works better than GSC?

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

17. BU Bioinformatics A Receptor-Ligand Complex

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

19. BU Bioinformatics Impact of Desolvation and Electrostatics

20. BU Bioinformatics Impact of Desolvation and Electrostatics

21. BU Bioinformatics 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. BU Bioinformatics 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. BU Bioinformatics 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. BU Bioinformatics 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. BU Bioinformatics 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/f rames.htm

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

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

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