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Rosetta Energy Function

Rosetta Energy Function. Glenn Butterfoss. Rosetta Energy Function. Major Classes: 1. Low resolution: Reduced atom representation Simple energy function Aggressively search conformational space 2. High resolution: Full atom More sophisticated energy function

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Rosetta Energy Function

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  1. Rosetta Energy Function Glenn Butterfoss

  2. Rosetta Energy Function Major Classes: 1. Low resolution: Reduced atom representation Simple energy function Aggressively search conformational space 2. High resolution: Full atom More sophisticated energy function “Local” search of conformational (and sequence) space

  3. Rosetta Energy Function Low resolution: Atom Model centroid reduction of side chains Energy function terms van der Waals repulsion “pair” terms (electrostatics) residue environment (prob of burial) 2º structure pairing terms (H-bonds) radius of gyration packing density Implicit terms fragments (local interactions)

  4. Rosetta Energy Function Low resolution: Atom Model centroid reduction of side chains Energy function terms van der Waals repulsion “pair” terms (electrostatics) residue environment (prob of burial) 2º structure pairing terms (H-bonds) radius of gyration packing density Implicit terms fragments (local interactions) In general … Weighted linear combination Energy = w1*term1 + w2*term2 + … Pair-wise decomposable Heavily trained on PDB statistics Discriminate “near native” vs “non native” No single low resolution score Several functions with different weights

  5. χ2 χ1 Rosetta Energy Function Low resolution: Atom Model centroid reduction of side chains Energy function terms van der Waals repulsion “pair” terms (electrostatics) residue environment (prob of burial) 2º structure pairing terms (H-bonds) radius of gyration packing density Implicit terms fragments (local interactions)

  6. E d Rosetta Energy Function Low resolution: Atom Model centroid reduction of side chains Energy function terms van der Waals repulsion “pair” terms (electrostatics) residue environment (prob of burial) 2º structure pairing terms (H-bonds) radius of gyration packing density Implicit terms fragments (local interactions) CLASH BAD!! Evaluate between Centoids and Backbone Atoms

  7. Rosetta Energy Function Low resolution: Atom Model centroid reduction of side chains Energy function terms van der Waals repulsion “pair” terms (electrostatics) residue environment (prob of burial) 2º structure pairing terms (H-bonds) radius of gyration packing density Implicit terms fragments (local interactions) Pair-wise probability based on PDB statistics (electrostatics) aa = residue type d = centroid distance (binned, interpolated) s = sequence seperation (must be > 8 res )

  8. Rosetta Energy Function Low resolution: Atom Model centroid reduction of side chains Energy function terms van der Waals repulsion “pair” terms (electrostatics) residue environment (prob of burial) 2º structure pairing terms (H-bonds) radius of gyration packing density Implicit terms fragments (local interactions) Probability of burial /exposure (solvation) neighbors within 10 Å of C binned by : 0-3, 4,5, … , >30 also interpolated

  9. Rosetta Energy Function Low resolution: Atom Model centroid reduction of side chains Energy function terms van der Waals repulsion “pair” terms (electrostatics) residue environment (prob of burial) 2º structure pairing terms (H-bonds) radius of gyration packing density Implicit terms fragments (local interactions) Optimize 2º orientation

  10. Rosetta Energy Function Low resolution: Atom Model centroid reduction of side chains Energy function terms van der Waals repulsion “pair” terms (electrostatics) residue environment (prob of burial) 2º structure pairing terms (H-bonds) radius of gyration packing density Implicit terms fragments (local interactions) Represent protein as vectors of 2 residue “strands” R2 N sheet vector C R1 O helix vector

  11. Rosetta Energy Function Low resolution: Atom Model centroid reduction of side chains Energy function terms van der Waals repulsion “pair” terms (electrostatics) residue environment (prob of burial) 2º structure pairing terms (H-bonds) radius of gyration packing density Implicit terms fragments (local interactions) Coordinate system  hb  v1 v2  r Scores selected to discriminate “near native structures for “non native”: Relative direction () Relative H-bond orientation (hb) Distance (r, r Number of sheets given number of strands Helix-Strand Packing

  12. Rosetta Energy Function Low resolution: Atom Model centroid reduction of side chains Energy function terms van der Waals repulsion “pair” terms (electrostatics) residue environment (prob of burial) 2º structure pairing terms (H-bonds) radius of gyration packing density Implicit terms fragments (local interactions) Promote a compact fold Used in earlier stages and for filtering

  13. Rosetta Energy Function Low resolution: Atom Model centroid reduction of side chains Energy function terms van der Waals repulsion “pair” terms (electrostatics) residue environment (prob of burial) 2º structure pairing terms (H-bonds) radius of gyration packing density Implicit terms fragments (local interactions) set of non-redundant protein structures LTSDELKAQWNTSTLVRHQEAGAS . . .

  14. Rosetta Energy Function Low resolution: Atom Model centroid reduction of side chains Energy function terms van der Waals repulsion “pair” terms (electrostatics) residue environment (prob of burial) 2º structure pairing terms (H-bonds) radius of gyration packing density Implicit terms fragments (local interactions) Extended protein chain Select a site N C + Fragment insertion C N + Fragment insertion N C

  15. Rosetta Energy Function High resolution: Atom Model full atom representation Energy function terms Rotamer (Dunbrack) Ramachandran Solvation (Lazaridius Karplus) Hydrogen bonding Lennard-Jones Pair (electrostatic) Reference energies In general … Weighted linear combination Energy = w1*term1 + w2*term2 + … Pair-wise decomposable Pre- tabulate energies Hybrid Statistical / MM-like score Weights trained for different applications

  16. χ2 χ1 Rosetta Energy Function High resolution: Atom Model full atom representation Energy function terms Rotamer (Dunbrack) Ramachandran Solvation (Lazaridius Karplus) Hydrogen bonding Lennard-Jones Pair (electrostatic) Reference energies

  17. Rosetta Energy Function High resolution: Atom Model full atom representation Energy function terms Rotamer (Dunbrack) Ramachandran Solvation (Lazaridius Karplus) Hydrogen bonding Lennard-Jones Pair (electrostatic) Reference energies rotamers experimental conformation rotamer

  18. χ2 χ1 Rosetta Energy Function High resolution: Atom Model full atom representation Energy function terms Rotamer (Dunbrack) Ramachandran Solvation (Lazaridius Karplus) Hydrogen bonding Lennard-Jones Pair (electrostatic) Reference energies Dunbrack and Cohen library Based on PDB statistics Backbone dependent Additional rotamers from standard deviations of distributions

  19. χ2 χ1 Rosetta Energy Function High resolution: Atom Model full atom representation Energy function terms Rotamer (Dunbrack) Ramachandran Solvation (Lazaridius Karplus) Hydrogen bonding Lennard-Jones Pair (electrostatic) Reference energies Local backbone energy ss = secondary structure Also used in some centroid refinement

  20. Rosetta Energy Function High resolution: Atom Model full atom representation Energy function terms Rotamer (Dunbrack) Ramachandran Solvation (Lazaridius Karplus) Hydrogen bonding Lennard-Jones Pair (electrostatic) Reference energies Simple solvation model Lazaridius Karplus (standard) Fast pair-wise additive Penalize burial of polar residues

  21. Rosetta Energy Function High resolution: Atom Model full atom representation Energy function terms Rotamer (Dunbrack) Ramachandran Solvation (Lazaridius Karplus) Hydrogen bonding Lennard-Jones Pair (electrostatic) Reference energies Simple solvation model (Special cases) Protein-DNA interactions: Generalized Born Protein-Ligand: Coulomb

  22. O O H Rosetta Energy Function High resolution: Atom Model full atom representation Energy function terms Rotamer (Dunbrack) Ramachandran Solvation (Lazaridius Karplus) Hydrogen bonding Lennard-Jones Pair (electrostatic) Reference energies H-bonding r Geometric H-bond potential 2 angles, 1 distance Based on PDB statistics

  23. Rosetta Energy Function High resolution: Atom Model full atom representation Energy function terms Rotamer (Dunbrack) Ramachandran Solvation (Lazaridius Karplus) Hydrogen bonding Lennard-Jones Pair (electrostatic) Reference energies VDW interactions r CHARMM radii Standard attractive potential Repulsive term linearized Note: command line options allow the repulsive term to be softened (radii reduced)

  24. Rosetta Energy Function High resolution: Atom Model full atom representation Energy function terms Rotamer (Dunbrack) Ramachandran Solvation (Lazaridius Karplus) Hydrogen bonding Lennard-Jones Pair (electrostatic) Reference energies Electrostatics Probability of finding residue types at give in distance Defined by C coordinates

  25. Rosetta Energy Function High resolution: Atom Model full atom representation Energy function terms Rotamer (Dunbrack) Ramachandran Solvation (Lazaridius Karplus) Hydrogen bonding Lennard-Jones Pair (electrostatic) Reference energies Correction for “folding” Unique “cost” for designing in each residue type G for bringing residue type into folded protein Optimized with sequence recovery trials of folded protein structures

  26. Rosetta Energy Function Xavier Rosetta Community Thanks

  27. Rosetta in Systems Biology Structure Prediction: Monte Carlo + Minimization search p(ΔE)? Energy

  28. Rosetta in Systems Biology Protein Design: Protocol: Packing: Pre-tabulate table of all pair-wise rotamer energies Monte Carlo search through rotamer / sequence space With docking and backbone movement: Iterate packing with (as above) with backbone / rigid body movements Possibly apply restraints docking, rmsd, disulfide, …

  29. Rosetta in Systems Biology Protein Design: Protocol: Filtering: Total energy Packing quality Avoid buried unsatisfied H-bonds (problem at interfaces)

  30. Rosetta Energy Function Low resolution: Atom Model centroid reduction of side chains Energy function terms van der Waals repulsion “pair” terms (electrostatics) residue environment (prob of burial) 2º structure pairing terms (H-bonds) radius of gyration packing density Implicit terms fragments (local interactions)

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