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?
R
L
Protein docking is the computational
determination of protein complex structure
from individual protein structures.
L
R
3. Bioinformatics
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.
5. Bioinformatics
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
10. Bioinformatics
Biomedical Engineering
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.
12. Bioinformatics
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
14. Bioinformatics
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
17. Bioinformatics
Biomedical Engineering
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
c
i
j
i
c
i
N
( ) ( ) ( )
2 2 2
1
27. Bioinformatics
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.
28. Bioinformatics
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!
