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Rosetta Energy Function Glenn Butterfoss

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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

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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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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 = w 1 *term 1 + w 2 *term 2 + … Pair-wise decomposable Heavily trained on PDB statistics Discriminate “near native” vs “non native” No single low resolution score Several functions with different weights

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Rosetta Energy Function 11 22 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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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) d E CLASH BAD!! Evaluate between Centoids and Backbone Atoms

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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 )

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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) neighbors within 10 Å of C binned by : 0-3, 4,5, …, >30 also interpolated Probability of burial /exposure (solvation)

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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

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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) N R1R1 R2R2 C O Represent protein as vectors of 2 residue “strands” sheet vector helix vector

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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 v1v1 v2v2 r hb 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

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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) Used in earlier stages and for filtering Promote a compact fold

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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) LTSDELKAQWNTSTLVRHQEAGASLTSDELKAQWNTSTLVRHQEAGAS set of non-redundant protein structures......

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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) NC + N C Fragment insertion Extended protein chain N C + Select a site Fragment insertion

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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 = w 1 *term 1 + w 2 *term 2 + … Pair-wise decomposable Pre- tabulate energies Hybrid Statistical / MM-like score Weights trained for different applications

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Rosetta Energy Function 11 22 High resolution: Atom Model full atom representation Energy function terms Rotamer (Dunbrack) Ramachandran Solvation (Lazaridius Karplus) Hydrogen bonding Lennard-Jones Pair (electrostatic) Reference energies

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experimental conformation rotamer 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

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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 11 22 Dunbrack and Cohen library Based on PDB statistics Backbone dependent Additional rotamers from standard deviations of distributions

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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 11 22 ss = secondary structure Local backbone energy Also used in some centroid refinement

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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 Fast pair-wise additive Penalize burial of polar residues Simple solvation model Lazaridius Karplus (standard)

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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 Protein-DNA interactions: Generalized Born Protein-Ligand: Coulomb Simple solvation model (Special cases)

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

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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 r CHARMM radii Standard attractive potential Repulsive term linearized Note: command line options allow the repulsive term to be softened (radii reduced) VDW interactions

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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 Probability of finding residue types at give in distance Defined by C coordinates Electrostatics

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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 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 Correction for “folding”

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Rosetta Energy Function Xavier Rosetta Community Thanks

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

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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, …

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

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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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