Protein Structure Prediction

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Protein Structure Prediction and Refinement
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If the models are good enough to predict peptide
structure. Protein Structure Refinement
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Why Refinement of Protein Structural Models.

• Homology models contain little additional
  information compared to the
• template structures (unless they can be refined).

• An inability to determine the relative merit of
  ab-initio models.

Bi-annual CASP competition CASP Critical
Assessment of techniques for protein Structure
Prediction
Aim To refine models from ROSETTA1 (currently
the best semi ab inito structure prediction
algorithm.)
1. Baker et al. J. Mol. Biol. (2001) 306,
1191-1199.
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Refinement of Protein Structural Models
Test-set 20 proteins used by Baker et al. to
test ROSETTA (J. Mol. Biol. (2001) 306,
1191-1199).

• For each protein 4 ROSETTA models released from
  ROSETTA
• The best (closest to experimental
  structure)
• The worst (furthest from experimental
  structure)
• 3. Random example
• 4. Random example

• Proceedure
• Build side-chains
• Simulate in explicit solvent
• Compare to the experimental structure (do
  we do better or worse).

• Controls
• Simulate experimental structure (NMR or
  x-ray).
• Simulate experimental structure with
  side-chains deleted and rebuilt.

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MD refinement of the best Rosetta model for
1AIF (mercury detoxification protein)
Refinement MD 100 ns
NMR structure
ROSETTA model
0.26 nm RMSD
0.16 nm RMSD
Fan Hao
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MD Refinement of Rosetta models for 1AIF
Refinement is systematic given an ability to
simulate on a relevant time scale.
Fan Hao
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ROSETTA models
after 5ns MD
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NMR structure
1.03 nm RMSD
0.90 nm RMSD
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0.92 nm RMSD
0.91 nm RMSD
1AIF
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Some improvement in 3 of 4 cases
Fan Hao
0.90 nm RMSD
0.63 nm RMSD
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MD refinement of an alternate ROSETTA model for
1afi
Refinement MD 5 ns
Refinement MD 400 ns
ROSETTA model
NMR structure
0.87 nm RMSD
0.76 nm RMSD
0.70 nm RMSD
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Refinement of an alternate model for 1afi
RMSD 0.87 nm
RMSD 0.70 nm
RMSD 0.76 nm
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Refinement of 1sro (PNPase)
ROSETTA model
NMR structure
0.87 nm RMSD
Fan Hao
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Refinement of 1sro (PNPase)
NMR
RMSD 0.88 nm
RMSD 0.70 nm
RMSD 0.67 nm