Protein Docking Rong Chen Boston University

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

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

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

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.

BU Bioinformatics Rotational Sampling Density

BU Bioinformatics Rotational Sampling Density

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

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

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

BU Bioinformatics 9i9i9i9i9i9i9i9i9i9i 9i9i9i9i9i9i9i9i9i9i 9i9i9i9i9i9i 9i9i9i9i9i9i 9i9i9i9i9i9i9i9i9i9i 9i9i9i9i9i9i9i9i9i9i i9i 119i9i9i9i i9i 1 R GSC L GSC Grid-based Shape Complementarity

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 Pairwise Shape Complementarity

BU Bioinformatics PSC vs. GSC on Success Rate

BU Bioinformatics PSC vs. GSC on Hit Count

BU Bioinformatics Why PSC works better than GSC?

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

BU Bioinformatics A Receptor-Ligand Complex

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

BU Bioinformatics Impact of Desolvation and Electrostatics

BU Bioinformatics Impact of Desolvation and Electrostatics

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)

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.

BU Bioinformatics GRAMM Ilya A. Vakser, State University of New York at Stony Brook. Geometric fit and hydrophobicity FFT Low resolution docking

BU Bioinformatics DOT Lynn F. Ten Eyck, University of California, San Diego. Grid-based shape complemetarity, elctrostatics FFT html

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. rames.htm

BU Bioinformatics HEX Dave Ritchie, University of Aberdeen, Aberdeen, Scotland, UK spherical polar Fourier correlations

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

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