Introduction

Goal:
• Given two protein structures,
predict how they form a complex
Protein-Protein
Docking

Thomas Funkhouser
Applications:
Princeton University
• Quaternary structure prediction
CS597A, Fall 2005 • Protein interaction prediction
• etc.

Introduction Introduction
Goal: Proteins are densely packed inside cell
• Given two protein structures, • 20-30% of total volume inside cell
predict how they form a complex

Applications:
• Quaternary structure prediction
• Protein interaction prediction Representation of the approximate numbers, shapes and density of
packing of macromolecules inside a cell of Escherichia coli.
• etc. (Illustration by David S Goodsell)
[Szilágyi05]

Introduction Protein Interaction Prediction

Many biological processes are controlled by
protein-protein interactions
• Signal transduction
• Transport
• Cellular motion

1
Outline Outline
Introduction Introduction
Binding analysis Binding analysis
Docking methods Docking methods
Evaluation Evaluation
Discussion Discussion

Binding Site Analysis Binding Site Analysis

Proteins sometimes
contact each other
in more than one
distinct patch
• One patch (46/70)
2ptc
• Two patches (18/70)
• More patches (6/70)

1dan

1toc [Chakrabarti02] [Jones00]

Binding Site Analysis Binding Site Analysis

Protein interfaces tend to bury 1320 ± 520 Å2 Some residues have higher propensity to be in site

[Chakrabarti02] [Chakrabarti02]

2
Binding Site Analysis Binding Site Analysis
Some residues have higher propensity to be in site Residues in protein-protein interfaces are often
better conserved than others

[Jones00] [Wodak04]

Binding Site Analysis Outline

Many residues Introduction
often contribute to
Binding analysis
binding energetics
Docking methods
Evaluation
Discussion

Mapping of ∆∆G of individual residues onto their location in the complexes [Bogan98]

Protein-Protein Docking Protein-Protein Docking

Bound docking: Similar to protein-ligand docking
• Search of conformations
• Scoring of energetics
Docking
Algorithm

Unbound docking:

[Gidalevitz]

3
Protein-Protein Docking Protein-Protein Docking
Main differences: Programs:
• Sites have … • 3D-Dock
§ Large, flat surfaces • HEX
§ Conservation, maybe
• GRAMM
§ Hydrophobic core
• PPD
• Binding energetics are usually dominated by …
§ Geometry
• DOT
§ Hydrophobicity • BIGGER
• Protein flexibility is important • DOCK
§ Side-chains • AutoDock
§ Backbone • FlexX
• Darwin
• ZDOCK

Protein-Protein Docking Pipeline Rigid Docking

Shape complementarity:

[Smith02] [Lesk&Sternberg] [Lesk&Sternberg]

Rigid Docking Rigid Docking

Electrostatic complementarity: Search methods:
• Exhaustive
• FFT

Rotations Translations

tstep rstep

[Lesk&Sternberg] FRED [Yang04]

4
Flexible Docking Outline
Search methods: Introduction
• Side-chain rotamer libraries
Binding analysis
• Monte Carlo algorithms
• Genetic algorithms Docking methods
Evaluation
Discussion

[Wang05]

Evaluation Methods Evaluation Methods

Metrics: Bound Ab - X-Ray Metrics:
• RMSD (usually Cα) Bound Ab - Predicted • RMSD (usually Cα)
• % of contacts predicted • % of contacts predicted

Unbound Amylase

[Lesk&Sternberg] [Janin05]

Evaluation Methods Evaluation Methods

Benchmarks: Benchmarks:
• CAPRI • CAPRI

X-Ray Structure Distribution of Centers of Mass

for Capri Target 08 for predicted Complexes
[Janin05] [Wodak04]

5
Discussion References
[Bogan98] A.A. Bogan, K.S. Thorn, "Anatomy of hot spots in protein interfaces," J. Mol. Biol., 280, 1998, pp. 1-9.
[Chakrabarti02] P. Chakrabarti, J. Janin, "Dissecting protein-protein recognition sites," Proteins: Structure, Function, and Genetics,
47, 3, 2002, pp. 334-343.
[Gidalevitz] Gidalevitz T, Biswas C, Ding H, Schneidman D, Wolfson HJ, Stevens F, Radford S, Argon Y. “Guiding “in vitro”
experiments with “in silico” predictions”, http://bioinfo3d.cs.tau.ac.il/Education/BioInfo04/LastLect/Docking-
grp94.ppt.
[Janin05] J. Janin, "Assessing predictions of protein-protein interaction: The CAPRI experiment," Protein Science, 14, 2005, pp.
278-283.
[Jones00] S. Jones, A. Marin, J.M. Thornton, "Protein domain interfaces: characterization and comparison with oligomeric

?
protein interfaces," Protein Engineering, 13, 2, 2000, pp. 77-82.
[Smith02] G.R. Smitth, M.J.E. Sternberg, "Prediction of protein-protein interactions by docking methods," Current Opinion in
Structural Biology, 12, 2002, pp. 28-35.
[Szilagyi05] A. Szilagyi, V. Grimm, A.K. Arakaki, J. Skolnick, "Prediction of physical protein-protein interactions," Phys. Biol., 2,
2005, pp. S1-S16.
[Wang05] C. Wang, O. Schueler-Furman, and D. Baker, "Improved side-chain modeling for protein-protein docking", Protein
Science, 14, 2005, pp. 1328-1339.
[Wodak04] S.J. Wodak, R. Mendez, "Prediction of protein-protein interactions: the CAPRI experiment, its evaluation and
implications," Current Opinion in Structural Biology, 14, 2004, pp. 242-249.