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Protein Structure Prediction and
Refinement
If the models are good enough to predict peptide structure.
Protein Structure Refinement
Why Refinement of Protein Structural Models.
• Homology models contain little additional information compared to the template structures (unless they can be refined).
Bi-annual CASP competitionCASP: Critical Assessment of techniques for protein Structure Prediction
• An inability to determine the relative merit of ab-initio models.
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.
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
1. The best (closest to experimental structure)2. The worst (furthest from experimental structure)3. Random example4. Random example
Proceedure:1. Build side-chains2. Simulate in explicit solvent3. Compare to the experimental structure (do we do better or worse).
Controls:1. Simulate experimental structure (NMR or x-ray).2. Simulate experimental structure with side-chains deleted and rebuilt.
Refinement of Protein Structural Models
MD refinement of the best Rosetta model for 1AIF(mercury detoxification protein)
NMR structure ROSETTA model
0.26 nm RMSD
RefinementMD 100 ns
0.16 nm RMSD
Fan Hao
MD Refinement of Rosetta models for 1AIF
Refinement is systematicgiven an ability to simulate
on a relevant time scale.
Fan Hao
NMR structure
ROSETTA models
2
3
4
0.90 nm RMSD
1.03 nm RMSD
0.91 nm RMSD
0.63 nm RMSD
0.92 nm RMSD
0.90 nm RMSD
after 5ns MD
1AIF
Some improvement in 3 of 4 cases
Fan Hao
ROSETTA model RefinementMD 5 ns
RefinementMD 400 ns
NMR structure
MD refinement of an alternate ROSETTA model for 1afi
0.87 nm RMSD 0.76 nm RMSD 0.70 nm RMSD
Refinement of an alternate model for 1afi
RMSD 0.87 nm
RMSD 0.76 nm
RMSD 0.70 nm
Refinement of 1sro(PNPase)
ROSETTA modelNMR structure
0.87 nm RMSD
Fan Hao
RMSD 0.88 nm
RMSD 0.67 nm RMSD 0.70 nm
NMRRefinement of 1sro
(PNPase)