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Rosetta: De Novo determination of protein structure
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Results and performance Application and Future Prospects Conclusion
Outline Background- Ab Initio predictions Rosetta Method Results and performance Application and Future Prospects Conclusion
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Simulate interactions between pairs of atoms
Background Ab Initio predictions Physics of atomic interactions Simulate interactions between pairs of atoms Very difficult Heuristic Methods Based on databses of known structures
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Background Homology modeling Similarity to known structure Easy if sequence similarity > 50% Many methods, still popular Sequence-structure bias key to predict structure from sequence?
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Beg, Borrow or Steal - Structures
The Folding Problem Search Problem Beg, Borrow or Steal - Structures Discrimination Problem Identification of native-like conformation
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Venn diagram of conceptual basis for Rosetta
Rosetta Method Natural folding process Local structure propensities Tertiary Structure Local Tertiary N Venn diagram of conceptual basis for Rosetta
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Secondary Structure Prediction
The Rosetta Protocol Sequence Secondary Structure Prediction 3 and 9 residues fragment selection Monte-Carlo fragment insertion Clustering and Filtering of decoys Full-atom refinement 3D Structure
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Multiple Sequence Alignment Consistent fragments of 2 lengths
Protocol Contd. Fragment Generation Secondary Structure Prediction PsiPred , PHD , DSC and JUFO + Multiple Sequence Alignment Consistent fragments of 2 lengths
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Polar Side Chain Interactions Hydrogen Bonding – Beta Strands
Scoring Functions Hydrophobic Burial Polar Side Chain Interactions Hydrogen Bonding – Beta Strands Hard Sphere Repulsion
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Clustering and Filtering of Decoys
Global Backbone RMSD Structure in largest Cluster Contact Order Cut-off Radius of Gyration Cut-off Empirical Formula Beta Strand Pairing
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Results Native Native Model Native Model Model
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More Results…
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Folding Pathway of Ubiquitin
Helix Formation – 12 fragments Beta hairpin – 460 fragments Native Fold – 760 fragments Final refinement – 1304 frags RMSD ~ 2.1 A
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Size of the proteins ~ 100 residues
Success and Failures Native Like Conformation ( 4-6 A ) are produced CASP results Size of the proteins ~ 100 residues Difficult topologies still not good Computationally expensive
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Future Prospectus and Applications RosettaNMR, RosettaNOE
With Minimal Experimental Constraints RosettaNMR, RosettaNOE 3D Structure without Resonance Assignments ITAS, MJ’s Program Integration with other Ab Initio programs HMMSTR and I-Sites
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Conclusion Low to medium resolution structure are possible using Rosetta method. These structure are good starting point for further refinement. Low Resolution structure can give insight to protein functions.
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Thank You!!
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