Protein Protein Docking
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Introduction Goal:
Protein-Protein Docking Thomas Funkhouser Princeton University CS597A, Fall 2005
Introduction Goal: • Given two protein structures, predict how they form a complex
• Given two protein structures, predict how they form a complex
Applications: • Quaternary structure prediction • Protein interaction prediction • etc.
Introduction Proteins are densely packed inside cell • 20-30% of total volume inside cell
Applications: • Quaternary structure prediction • Protein interaction prediction • etc.
Introduction
Representation of the approximate numbers, shapes and density of packing of macromolecules inside a cell of Escherichia coli. (Illustration by David S Goodsell)
[Szilágyi05]
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) • Two patches (18/70) • More patches (6/70)
2ptc
1dan 1toc
[Chakrabarti02]
Binding Site Analysis
[Jones00]
Binding Site Analysis
Protein interfaces tend to bury 1320 ± 520 Å2
[Chakrabarti02]
Some residues have higher propensity to be in site
[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]
Binding Site Analysis
[Wodak04]
Outline
Many residues often contribute to binding energetics
Introduction Binding analysis 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 …
• • • • • • • • • • •
§ Large, flat surfaces § Conservation, maybe § Hydrophobic core
• Binding energetics are usually dominated by … § Geometry § Hydrophobicity
• Protein flexibility is important § Side-chains § Backbone
Protein-Protein Docking Pipeline
3D-Dock HEX GRAMM PPD DOT BIGGER DOCK AutoDock FlexX Darwin ZDOCK
Rigid Docking Shape complementarity:
[Smith02] [Lesk&Sternberg]
Rigid Docking
[Lesk&Sternberg]
Rigid Docking
Electrostatic complementarity:
Search methods: • Exhaustive • FFT
Rotations
Translations
tstep
[Lesk&Sternberg]
rstep
FRED [Yang04]
4
Flexible Docking
Outline
Search methods:
Introduction
• Side-chain rotamer libraries • Monte Carlo algorithms • Genetic algorithms
Binding analysis Docking methods Evaluation Discussion
[Wang05]
Evaluation Methods Metrics: • RMSD (usually Cα) • % of contacts predicted
Evaluation Methods Bound Ab - X-Ray Bound Ab - Predicted
Metrics: • RMSD (usually Cα) • % of contacts predicted
Unbound Amylase [Lesk&Sternberg]
Evaluation Methods
[Janin05]
Evaluation Methods
Benchmarks:
Benchmarks:
• CAPRI
• CAPRI
[Janin05]
X-Ray Structure for Capri Target 08
Distribution of Centers of Mass for predicted Complexes
[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/Dockinggrp94.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.
6
Protein-Protein Docking Thomas Funkhouser Princeton University CS597A, Fall 2005
Introduction Goal: • Given two protein structures, predict how they form a complex
• Given two protein structures, predict how they form a complex
Applications: • Quaternary structure prediction • Protein interaction prediction • etc.
Introduction Proteins are densely packed inside cell • 20-30% of total volume inside cell
Applications: • Quaternary structure prediction • Protein interaction prediction • etc.
Introduction
Representation of the approximate numbers, shapes and density of packing of macromolecules inside a cell of Escherichia coli. (Illustration by David S Goodsell)
[Szilágyi05]
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) • Two patches (18/70) • More patches (6/70)
2ptc
1dan 1toc
[Chakrabarti02]
Binding Site Analysis
[Jones00]
Binding Site Analysis
Protein interfaces tend to bury 1320 ± 520 Å2
[Chakrabarti02]
Some residues have higher propensity to be in site
[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]
Binding Site Analysis
[Wodak04]
Outline
Many residues often contribute to binding energetics
Introduction Binding analysis 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 …
• • • • • • • • • • •
§ Large, flat surfaces § Conservation, maybe § Hydrophobic core
• Binding energetics are usually dominated by … § Geometry § Hydrophobicity
• Protein flexibility is important § Side-chains § Backbone
Protein-Protein Docking Pipeline
3D-Dock HEX GRAMM PPD DOT BIGGER DOCK AutoDock FlexX Darwin ZDOCK
Rigid Docking Shape complementarity:
[Smith02] [Lesk&Sternberg]
Rigid Docking
[Lesk&Sternberg]
Rigid Docking
Electrostatic complementarity:
Search methods: • Exhaustive • FFT
Rotations
Translations
tstep
[Lesk&Sternberg]
rstep
FRED [Yang04]
4
Flexible Docking
Outline
Search methods:
Introduction
• Side-chain rotamer libraries • Monte Carlo algorithms • Genetic algorithms
Binding analysis Docking methods Evaluation Discussion
[Wang05]
Evaluation Methods Metrics: • RMSD (usually Cα) • % of contacts predicted
Evaluation Methods Bound Ab - X-Ray Bound Ab - Predicted
Metrics: • RMSD (usually Cα) • % of contacts predicted
Unbound Amylase [Lesk&Sternberg]
Evaluation Methods
[Janin05]
Evaluation Methods
Benchmarks:
Benchmarks:
• CAPRI
• CAPRI
[Janin05]
X-Ray Structure for Capri Target 08
Distribution of Centers of Mass for predicted Complexes
[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/Dockinggrp94.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.
6
