This document discusses protein docking, which is the computational determination of protein complex structures from individual protein structures. It describes challenges in protein docking like large search spaces and protein flexibility. The document outlines an integrated approach to protein docking that uses shape complementarity functions, desolvation energies, electrostatic interactions, and post-processing techniques. Evaluation on benchmark datasets shows a 60% success rate when 10 predictions are submitted. Future work proposed includes developing an automatic docking server and improving post-processing methods.

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

2. Bioinformatics
Biomedical Engineering
What is Protein Docking?
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Protein docking is the computational
determination of protein complex structure
from individual protein structures.
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Biomedical Engineering
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.

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Biomedical Engineering
Ubiquitination

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Biomedical Engineering
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. Bioinformatics
Biomedical Engineering
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. Bioinformatics
Biomedical Engineering
Protein-Protein Interaction
Thermodynamics
Energy
Free
Binding
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RL
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G 
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water

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The Lowest Binding Free
Energy G
water
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9. General Derivations

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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.

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

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Biomedical Engineering
Divide and Conquer
• Initial stage of unbound docking
– 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

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Biomedical Engineering
An Effective Binding Free
Energy Function
vdW desol elec const
vdW
desol
elec
const
ΔG=ΔE +ΔG +ΔE +ΔG
ΔE :
ΔG :
ΔE :
ΔG :
van der Waals energy; Shape complementarity
Desolvation energy; Hydrophobicity
Electrostatic interaction energy
Translational, rotational and vibrational free energy changes
desol
ΔG = N ΔG
N :
ΔG :
i i
i
i
i

Number of atoms of type i
Desolvation energy for an atom of type i

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Biomedical Engineering
Fast Fourier Transform
Increase the speed by 107
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Correlation
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IFFT
FFT
FFT
Surface Interior Binding Site

16. DOCK
by
Kuntz
et
al.

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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
RMSD
x x y y z z
N
j
i
j
i
c
i
j
i
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i
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i
N

    

( ) ( ) ( )
2 2 2
1

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23
16
10
6
0
5
10
15
20
25
Enzyme/Inihbitor Antibody/Antigen Others Difficult Cases
Docking Benchmark
55 non-redundant complexes
http://zlab.bu.edu/~rong/dock/

19. A Novel Shape Complementarity Function
0%
10%
20%
30%
40%
50%
60%
70%
80%
90%
100%
1 10 100 1000
Number of Predictions
Success
Rate
Grid-based shape complementarity (GSC)
GSC+Desolvation+Electrostatics
Pairwise shape complementarity (PSC)
PSC +Desolvation+Electrostatics

20. Post-Processing
Using
RDOCK

21. CAPRI Results
Target
Total
Contacts
Top Predictions
Our
Prediction
1 52 17 (1st) 5
2 52 27 (2nd) 50 (1st)
3 62 45 (1st), 43 (2nd) 37 (3rd)
4 58 1 (1st) 0
5 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

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Biomedical Engineering
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.

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Biomedical Engineering
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!