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

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

3. 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.

4. Ubiquitination

5. 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?

6. 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

7. Protein-Protein Interaction ThermodynamicsL
water

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

9. General Derivations

10. 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.

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

12. 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

13. Energy Components

14. 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

15. Fast Fourier TransformY
Correlation X
IFFT
FFT L
Surface
Interior
Binding Site
Increase the speed by 107

16. DOCK by Kuntz et al.

17. 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

18. Docking Benchmark 55 non-redundant complexes

20. Post-Processing Using RDOCK

21. CAPRI Results Target Total Contacts Top Predictions Our Prediction 152
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)

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

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

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

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

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

27. 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.

28. 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!