An Integrated Approach to Protein-Protein Docking Zhiping Weng Department of Biomedical Engineering Bioinformatics Program Boston University

What is Protein Docking? Protein docking is the computational determination of protein complex structure from individual protein structures. L R R L

Motivation Biological activity depends on the specific recognition of proteins. Understand protein interaction networks in a cell Yield insight to thermodynamics of molecular recognition The experimental determination of protein-protein complex structures remains difficult.

Ubiquitination

Experimental Tools for Studying Protein-Protein Interactions 3-D structures of protein-protein complexes: X-ray crystallography & NMR Binding affinity between two proteins: SPR, titration assays Mutagenesis and its affect on binding Yeast 2-hybrid system Protein Chips?

Computational Tools for Studying Protein-Protein Interactions Protein docking Binding affinity calculation Analysis of site-specific mutation experiments Protein design The kinetics of protein-protein interactions

Protein-Protein Interaction Thermodynamics L water

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

General Derivations

Two kinds of docking problems Bound docking The complex structure is known. The receptor and the ligand in the complex are pulled apart and reassembled. Unbound docking Individually determined protein structures are used.

Challenges Large search space Imperfect understanding of thermodynamics Protein flexibility Heterogeneities in protein interactions

Divide and Conquer Initial stage of unbound docking Post-processing Assume minimum binding site information Try to predict as many near-native structures (hits) as possible in the top 1000, for as many complexes as possible Post-processing Re-rank the 1000 structures in order to pick out near-native structures

Energy Components

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 atoms of type i Desolvation energy for an atom of type i

Fast Fourier Transform Y Correlation X IFFT FFT L Surface Interior Binding Site Increase the speed by 107

DOCK by Kuntz et al.

Evaluate Performance Gold Standard: Crystal structure of the complex A near-native structure (hit): RMSD of Ca after superposition < 2.5 Å Success rate: Given some number of predictions, percentage of complexes with at least one hit

Docking Benchmark 55 non-redundant complexes http://zlab.bu.edu/~rong/dock/

Post-Processing Using RDOCK

CAPRI Results Target Total Contacts Top Predictions Our Prediction 1 52 17 (1st) 5 2 27 (2nd) 50 (1st) 3 62 45 (1st), 43 (2nd) 37 (3rd) 4 58 1 (1st) 64 10 (1st) 4 (2nd) 6 65 60(1st) 18 7 37 30(2nd,3rd), 29(4th,5th) 31(1st)

Target 2: Antibody/VP6 Red: Crystal Structure Blue: Prediction 50/52; 1st

Target 7: T Cell Receptor / Toxin Red: Crystal Structure Blue: Prediction 31/37, 1st

Target 3: Antibody/Hemagglutinin Red: Crystal Structure Blue: Prediction 37/62, 3rd

Target 6: Camelide Antibody/a amylase Red: Crystal Structure Blue: Prediction 18/65

Target 1:Hpr/HPrK Red: Crystal Structure Blue: Prediction 5/52

Summary Conformational change tolerant target functions are needed for unbound docking We need to balance shape complementarity, desolvation, electrostatics components If we submit 10 predictions, we have a 60% success rate.

Future Work An automatic protein-protein docking server Large scale comparison of all docking algorithms on the benchmark Post processing with binding site information, conformation space search, clustering and detailed free energy calculation Make predictions!