rosetta energy function glenn butterfoss. rosetta energy function major classes: 1. low resolution:...
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![Page 1: Rosetta Energy Function Glenn Butterfoss. Rosetta Energy Function Major Classes: 1. Low resolution: Reduced atom representation Simple energy function](https://reader030.vdocuments.us/reader030/viewer/2022033106/56649cb85503460f9497e3f4/html5/thumbnails/1.jpg)
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
![Page 3: Rosetta Energy Function Glenn Butterfoss. Rosetta Energy Function Major Classes: 1. Low resolution: Reduced atom representation Simple energy function](https://reader030.vdocuments.us/reader030/viewer/2022033106/56649cb85503460f9497e3f4/html5/thumbnails/3.jpg)
Rosetta Energy FunctionLow 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)
![Page 4: Rosetta Energy Function Glenn Butterfoss. Rosetta Energy Function Major Classes: 1. Low resolution: Reduced atom representation Simple energy function](https://reader030.vdocuments.us/reader030/viewer/2022033106/56649cb85503460f9497e3f4/html5/thumbnails/4.jpg)
Rosetta Energy FunctionLow 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
![Page 5: Rosetta Energy Function Glenn Butterfoss. Rosetta Energy Function Major Classes: 1. Low resolution: Reduced atom representation Simple energy function](https://reader030.vdocuments.us/reader030/viewer/2022033106/56649cb85503460f9497e3f4/html5/thumbnails/5.jpg)
Rosetta Energy Function
χ1
χ2
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)
![Page 6: Rosetta Energy Function Glenn Butterfoss. Rosetta Energy Function Major Classes: 1. Low resolution: Reduced atom representation Simple energy function](https://reader030.vdocuments.us/reader030/viewer/2022033106/56649cb85503460f9497e3f4/html5/thumbnails/6.jpg)
Rosetta Energy FunctionLow 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!!
€
(rij2 − dij
2)2
r ijj<i
∑i
∑ ;dij < rij
€
d = distance
r = radii∑
Evaluate between Centoids and Backbone Atoms
![Page 7: Rosetta Energy Function Glenn Butterfoss. Rosetta Energy Function Major Classes: 1. Low resolution: Reduced atom representation Simple energy function](https://reader030.vdocuments.us/reader030/viewer/2022033106/56649cb85503460f9497e3f4/html5/thumbnails/7.jpg)
Rosetta Energy FunctionLow 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)
€
−lnP(aai,aa j | sijdij )
P(aai | sijdij )P(aai | sijdij )
⎡
⎣ ⎢
⎤
⎦ ⎥
j>i
∑i
∑
aa = residue typed = centroid distance (binned, interpolated)s = sequence seperation (must be > 8 res )
![Page 8: Rosetta Energy Function Glenn Butterfoss. Rosetta Energy Function Major Classes: 1. Low resolution: Reduced atom representation Simple energy function](https://reader030.vdocuments.us/reader030/viewer/2022033106/56649cb85503460f9497e3f4/html5/thumbnails/8.jpg)
Rosetta Energy FunctionLow 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€
−ln P(aai | neighborsi)[ ]i
∑
Probability of burial /exposure(solvation)
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Rosetta Energy FunctionLow 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
![Page 10: Rosetta Energy Function Glenn Butterfoss. Rosetta Energy Function Major Classes: 1. Low resolution: Reduced atom representation Simple energy function](https://reader030.vdocuments.us/reader030/viewer/2022033106/56649cb85503460f9497e3f4/html5/thumbnails/10.jpg)
Rosetta Energy FunctionLow 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
R1
R2
C
O
Represent protein as vectors of2 residue “strands”
sheet vector
helix vector
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Rosetta Energy FunctionLow 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
v1
v2
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 FunctionLow 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€
RG = dij2
Density = −lnPcompact (neighborsi,sh )
Prandom (neighborsi,sh )
⎡
⎣ ⎢
⎤
⎦ ⎥
sh
∑i
∑
Promote a compact fold
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Rosetta Energy FunctionLow 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)
LTSDELKAQWNTSTLVRHQEAGAS
set of non-redundantprotein structures
.
.
.
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Rosetta Energy FunctionLow 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 C+
NC
Fragment insertion
Extended protein chain
NC
+
Select a site
Fragment insertion
![Page 15: Rosetta Energy Function Glenn Butterfoss. Rosetta Energy Function Major Classes: 1. Low resolution: Reduced atom representation Simple energy function](https://reader030.vdocuments.us/reader030/viewer/2022033106/56649cb85503460f9497e3f4/html5/thumbnails/15.jpg)
Rosetta Energy FunctionHigh 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
![Page 16: Rosetta Energy Function Glenn Butterfoss. Rosetta Energy Function Major Classes: 1. Low resolution: Reduced atom representation Simple energy function](https://reader030.vdocuments.us/reader030/viewer/2022033106/56649cb85503460f9497e3f4/html5/thumbnails/16.jpg)
Rosetta Energy Function
χ1
χ2
High resolution:
Atom Model
full atom representation
Energy function terms
Rotamer (Dunbrack)
Ramachandran
Solvation (Lazaridius Karplus)
Hydrogen bonding
Lennard-Jones
Pair (electrostatic)
Reference energies
![Page 17: Rosetta Energy Function Glenn Butterfoss. Rosetta Energy Function Major Classes: 1. Low resolution: Reduced atom representation Simple energy function](https://reader030.vdocuments.us/reader030/viewer/2022033106/56649cb85503460f9497e3f4/html5/thumbnails/17.jpg)
experimental conformation
rotamer
Rosetta Energy FunctionHigh resolution:
Atom Model
full atom representation
Energy function terms
Rotamer (Dunbrack)
Ramachandran
Solvation (Lazaridius Karplus)
Hydrogen bonding
Lennard-Jones
Pair (electrostatic)
Reference energies
rotamers
![Page 18: Rosetta Energy Function Glenn Butterfoss. Rosetta Energy Function Major Classes: 1. Low resolution: Reduced atom representation Simple energy function](https://reader030.vdocuments.us/reader030/viewer/2022033106/56649cb85503460f9497e3f4/html5/thumbnails/18.jpg)
Rosetta Energy FunctionHigh resolution:
Atom Model
full atom representation
Energy function terms
Rotamer (Dunbrack)
Ramachandran
Solvation (Lazaridius Karplus)
Hydrogen bonding
Lennard-Jones
Pair (electrostatic)
Reference energies
χ1
χ2
Dunbrack and Cohen library
€
−lnP(rotamer |φi,ψ i)P(aai |φi,ψ i)
P(aai)
⎡
⎣ ⎢
⎤
⎦ ⎥
i
∑
Based on PDB statistics
Backbone dependent
Additional rotamers from standard deviations of distributions
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Rosetta Energy FunctionHigh resolution:
Atom Model
full atom representation
Energy function terms
Rotamer (Dunbrack)
Ramachandran
Solvation (Lazaridius Karplus)
Hydrogen bonding
Lennard-Jones
Pair (electrostatic)
Reference energies
χ1
χ2
€
−ln P(φi,ψ i | aai,ssi)[ ]i
∑ss = secondary structure
Local backbone energy
Also used in some centroid refinement
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Rosetta Energy FunctionHigh 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 modelLazaridius Karplus
(standard)
![Page 21: Rosetta Energy Function Glenn Butterfoss. Rosetta Energy Function Major Classes: 1. Low resolution: Reduced atom representation Simple energy function](https://reader030.vdocuments.us/reader030/viewer/2022033106/56649cb85503460f9497e3f4/html5/thumbnails/21.jpg)
Rosetta Energy FunctionHigh 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
![Page 23: Rosetta Energy Function Glenn Butterfoss. Rosetta Energy Function Major Classes: 1. Low resolution: Reduced atom representation Simple energy function](https://reader030.vdocuments.us/reader030/viewer/2022033106/56649cb85503460f9497e3f4/html5/thumbnails/23.jpg)
Rosetta Energy FunctionHigh 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
![Page 24: Rosetta Energy Function Glenn Butterfoss. Rosetta Energy Function Major Classes: 1. Low resolution: Reduced atom representation Simple energy function](https://reader030.vdocuments.us/reader030/viewer/2022033106/56649cb85503460f9497e3f4/html5/thumbnails/24.jpg)
Rosetta Energy FunctionHigh 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
![Page 25: Rosetta Energy Function Glenn Butterfoss. Rosetta Energy Function Major Classes: 1. Low resolution: Reduced atom representation Simple energy function](https://reader030.vdocuments.us/reader030/viewer/2022033106/56649cb85503460f9497e3f4/html5/thumbnails/25.jpg)
Rosetta Energy FunctionHigh 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 CommunityThanks
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Rosetta in Systems Biology
Structure Prediction:
Monte Carlo + Minimization search
p(E)?
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 FunctionLow 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)
€
−lnP aai,aa j | dij( )
P(aa
⎡
⎣ ⎢ ⎢
⎤
⎦ ⎥ ⎥
∑∑