Protein docking


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Physical background of protein

Protein docking

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Protein docking

  1. 1. Protein dockingSaramita De Chakravarti12/14/2012
  2. 2. Outline Physical background of protein Protein docking
  3. 3. Quantum Mechanism (QM) Electrons Nuclei Wave functions instead of Newton Eq. High computation cost Ab initio N4N is # of base functions Semi-empirical N3 Molecule of a couple of hundreds atoms Pico-second(10-12s) behavior
  4. 4. Molecular Mechanism (MM) Atoms Newton equations Parameters from experiment and QM force field System with 100,000 atoms µs (10-6s) behavior
  5. 5. Force field+−+−= ∑∑ 22)()( eqangleeqbondsb krrkU θθθ])[()]cos(1[2 612ijjiijiji ij ijijdihedral nnrqqrBrAnV⋅+−+−+ ∑∑∑ ∑ > εγφkb – bond parameterkө --- angle parameterVn --- dihedral energy barrierVan Der Waal radiiPartial charge set
  6. 6. Solvent effect Oil in water Hydrophobic interactions Alcohol in water Hydrophilic interactions Explicit water Solvent Accessible Surface Surface Complementarity
  7. 7. Twenty Amino Acids
  8. 8. SidechainsThe amino acids vary in their side chains (indicated in blue in the diagram).The eight amino acids in the orange area are nonpolar and hydrophobic.The other amino acids are polar and hydrophilic ("water loving").The two amino acids in the magenta box are acidic ("carboxy" group in the side chain).The three amino acids in the light blue box are basic ("amine" group in the side chain).
  9. 9. Peptide bonds
  10. 10. Proteins Primary structure Secondary structure Tertiary structure Quaternary structure
  11. 11. Important forces Weak forces Delicate balance Electrostatic (hydrogen bonds, saltbridges) Hydrophobic (sidechain packing)
  12. 12. Protein docking
  13. 13. Contents Why Is Docking Important? Why Is Docking Hard? Docking Scoring Criteria Docking Search Strategies CAPRI Participants & Algorithms Lessons Learnt From CAPRI Selected Docking References
  14. 14. Why Is Docking Important? Better understand the Machinery of Life Enzyme-inhibitor class Antibody-antigen class Others Engineered Protein Enzymes Protein Therapies Drug targets
  15. 15. Why Is Docking A Hard Problem? Large Search Space ! Rigid Body Docking: 6D Flexible Docking: 3N (N normal modes) Structure Space: Continuous
  16. 16. Criteria for Good DockingOrientations Low Free Energy Low Pseudo-Energy Based On force field Large Surface Burial Small van der Waals Overlaps Good H-Bonding Good Charge Complementarity Polar/Polar Contacts Favoured Polar/Non-Polar Contacts Disfavoured
  17. 17. Docking Search Strategies Pseudo Random Simulated Annealing / Monte Carlo Genetic Algorithms Directed Search Geometric Hashing Spherical Harmonic Surface Triangles
  18. 18. Docking Search Strategies Brute-Force Search Explicit Grid Correlations Fast Fourier Transform (FFT) Correlations Refinement Phase Classical or Soft Potentials (+/- Electrostatics) Desolvation, Solvent Dipoles... Visual Inspection!!
  19. 19. CAPRI Critical Assessment of PRedictedInteractions targets available (unbounded/bounded) Bounded (rigid) Unbounded (non-rigid) International groups participated
  20. 20. Cartesian Grid CorrelationsBasic Principles
  21. 21. dPNAS 1992 89 pp. 2195-2199
  22. 22. Electrostatic complementarityJMB 1997 272, pp 106-120
  23. 23. The electric field by protein A
  24. 24. Correlation functionBinary filter to remove false positive geometries
  25. 25. Lessons Learnt From CAPRI Antibodies Often Bind Near AntigensActive Site Expect Large Conformational Changein Enzyme/Inhibitor Docking Develop Better Models of Flexibility
  26. 26. Future Challenges ForDocking Better Scoring Functions High-Throughput Screening Tractable Models of Flexibility
  27. 27. Reference ReviewsHalperin et al.; Proteins, 47 409-443 (2002)Smith & Sternberg; COSB, 12 28-35 (2002) CAPRI AlgorithmsChen & Weng; Proteins, 47 281-294 (2002)Fernandez-Recio et al.; Prot Sci, 11 280-291 (2002)Gardiner et al.; Proteins, 44 44-56 (2001)Camacho et al.; Proteins, 40 525-537 (2000)Palma et al.; Proteins, 39 372-384 (2000)Ritchie & Kemp; Proteins, 39 178-194 (2000)Gabb et al.; J Mol Biol 272 106-120 (1997)Vakser; Proteins, S1 226-230 (1997)Abagyan et al.; J Comp Chem, 15 488-506 (1994)Norel et al.; Prot Eng 7 39-46 (1994)Katchalski-Katzir et al.; PNAS, 89 2195-2199 (1992)