Protein-Protein Docking

Transcription

1 Protein-Protein Docking Goal: Given two protein structures, predict how they form a complex Thomas Funkhouser Princeton University CS597A, Fall 2005 Applications: Quaternary structure prediction Protein interaction prediction etc. Goal: Given two protein structures, predict how they form a complex Proteins are densely packed inside cell 20-30% of total volume inside cell Applications: Quaternary structure prediction Protein interaction prediction etc. Representation of the approximate numbers, shapes and density of packing of macromolecules inside a cell of Escherichia coli. (Illustration by David S Goodsell) [Szilágyi05] Many biological processes are controlled by protein-protein interactions Signal transduction Transport Cellular motion Protein Interaction Prediction 1

2 Outline Outline Proteins sometimes contact each other in more than one distinct patch One patch (46/70) Two patches (18/70) More patches (6/70) 2ptc 1toc 1dan [Chakrabarti02] [Jones00] Protein interfaces tend to bury 1320 ± 520 Å 2 Some residues have higher propensity to be in site [Chakrabarti02] [Chakrabarti02] 2

3 Some residues have higher propensity to be in site Residues in protein-protein interfaces are often better conserved than others [Jones00] [Wodak04] Many residues often contribute to binding energetics Outline Mapping of G of individual residues onto their location in the complexes [Bogan98] Protein-Protein Docking Bound docking: Protein-Protein Docking Similar to protein-ligand docking Search of conformations Scoring of energetics Docking Algorithm Unbound docking: [Gidalevitz] 3

4 Protein-Protein Docking Main differences: 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 Programs: 3D-Dock HEX GRAMM PPD DOT BIGGER DOCK AutoDock FlexX Darwin ZDOCK Protein-Protein Docking Pipeline Rigid Docking Shape complementarity: [Smith02] [Lesk&Sternberg] [Lesk&Sternberg] Rigid Docking Electrostatic complementarity: Rigid Docking Search methods: Exhaustive FFT Rotations Translations tstep rstep [Lesk&Sternberg] FRED [Yang04] 4

5 Flexible Docking Search methods: Side-chain rotamer libraries Monte Carlo algorithms Genetic algorithms Outline [Wang05] Metrics: RMSD (usually Cα) % of contacts predicted Bound Ab - X-Ray Bound Ab - Predicted Metrics: RMSD (usually Cα) % of contacts predicted Unbound Amylase [Lesk&Sternberg] [Janin05] Benchmarks: CAPRI Benchmarks: CAPRI [Janin05] X-Ray Structure for Capri Target 08 Distribution of Centers of Mass for predicted Complexes [Wodak04] 5

6 References? [Bogan98] A.A. Bogan, K.S. Thorn, "Anatomy of hot spots in protein interfaces," J. Mol. Biol., 280, 1998, pp [Chakrabarti02] P. Chakrabarti, J. Janin, "Dissecting protein-protein recognition sites," Proteins: Structure, Function, and Genetics, 47, 3, 2002, pp [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 [Smith02] G.R. Smitth, M.J.E. Sternberg, "Prediction of protein-protein interactions by docking methods," Current Opinion in Structural Biology, 12, 2002, pp [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 [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