Protein-Protein Docking by murplelake83


                                               • Given two protein structures,
                                                 predict how they form a complex

                 Thomas Funkhouser
                 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

 • 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)

Introduction                                  Protein Interaction Prediction
Many biological processes are controlled by
protein-protein interactions
 • Signal transduction
 • Transport
 • Cellular motion

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)


                             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]

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

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

Unbound docking:


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]

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


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]

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”,
                 [Janin05]     J. Janin, "Assessing predictions of protein-protein interaction: The CAPRI experiment," Protein Science, 14, 2005, pp.
                 [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.


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