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Protein

Protein. By Thomas Huber 23 November 2001 Alexandra Headland. In double vision when drunk. What would we like to be able to calculate/predict/model?. Which proteins are expressed? Alternative splicing Post-translational modifications What is a protein’s evolution?

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Protein

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  1. Protein By Thomas Huber 23 November 2001 Alexandra Headland In double vision when drunk

  2. What would we like to be able to calculate/predict/model? • Which proteins are expressed? • Alternative splicing • Post-translational modifications • What is a protein’s evolution? • Ancestor/descendant relationships (Phylogeny) • What is a protein’s structure? • Does a sequence adopt a new/known fold? • What is a protein’s function? • Functional annotation • How stable is a protein? • Thermodynamics • How fast does a protein work/fold? • Kinetics • Which molecules do interact? • Protein interaction networks

  3. Three basic choices in molecular modelling • Representation • Which degrees of freedom are treated explicitly • Scoring • Which scoring function (force field) • Searching • Which method to search or sample conformational space Two Linages of Protein Structure Prediction • The physicist’s approach • Thermodynamics: Structures with low energy are more likely • The biologist’s approach • Similar sequences  similar structures

  4. Why is the physicist’s approach better? Biologist’s concept: Homologous sequences fold into similar structures Needs reference sequence Physicist’s concept: Doing what nature does (forces due to structure) Reference free

  5. Challenge I:The force field (score function) • Simple task • Find a residue interaction function (parameters) that can tell good sequence-structure matches • from bad ones • Approaches • Scoring functions based on statistics • Scoring functions based on optimisation • Scoring functions based on physics • Combinations of all above • Limitations • Limit of accuracy due to resolution of representation • 20-40% “success” rate in hard fold recognition predictions

  6. Challenge IIPrediction of Structure • Individual proteins (for understanding) • ATPase, RNA-Polymerases • Peptide folding on non-linear lattices • Lots of proteins (structural genomics) • Predicted models NOT good enough for molecular replacement in Xtallography! • Fragment detection for initial phases?? • Use of structure factors in model search?? • BUT, models are useful in NMR process and for biochemists How to improve models? • Incomplete (quick&cheap) experimental constraints • Crosslinking + MS • Incomplete data from NMR (1, 1J, 3J) • Iterative refinement • Assignment using models

  7. Challenge IIIInverse Folding Given a structure, is there a “better” sequence? • Many industrial applications metallochaperone ribosomal protein GlnB 11% 8% papillomavirus DNA binding domain acylphosphatase 11% 10%

  8. Whazon 2002Opportunities for Collaborations • CASP5: The protein structure prediction Olympics (4th participation) • Protein score function based on Gaussian mixture models • Molecular simulations • On and off lattices • Evolutionary analysis based on sequence, structure and energetics • E.g. ATPase • Structural genomics • Please introduce me to someone with a MS!! • Mathematician in Fourier space wanted!! • Inverse folding • Want to design a new protein and can make it?

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