Deborah L Crittenden Why proteins Molecular machinery of life eg ATP synthase enzyme dualaction molecular motor ion pump chemical factory The protein structure problem Human proteome ID: 1009588
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1. Balloon-based mutagenesis & protein foldingDeborah L. Crittenden
2. Why proteins?Molecular machinery of life e.g. ATP synthase:enzymedual-action molecular motorion pumpchemical factory
3. The protein structure problemHuman proteome: ~ 1,000,000 proteinsSolved structures: ~ 8,000 since 1972 ~ 1,000 per year for last 3 years
4. Computational solutionsDe novo protein folding‘brute force’‘crowd sourcing’Template-basedhomology modellingprotein threading
5. A new approachGradual change is good
6. Ballooning
7. Ballooning
8. Ballooning
9. Ballooningx
10. Ballooning
11. Ballooning
12. Ballooning
13. Ballooning
14. Ballooning
15. TechnicalitiesStepwise scaling of:bond lengthselectrostatic interaction energyEnergy minimizationAmoebaPro polarizable force field Tinker MM packageNumber of steps ∝ size of residue
16. ConsiderationsSidechain/whole residue replacementRotamersSolvationCounterionsMinimise vs optimise?
17. Case study: Trypsin inhibitor
18. Case study: Trypsin inhibitor
19. And the winner is: # 4
20. Predicting native conformersLowest energy solution?
21. Predicting native conformersLowest energy solution?Least affected by overgrowing?
22. Predicting native conformersLowest energy solution?Least affected by overgrowing?ΔΕ = Eovergrow - Egrow
23. Predicting native conformersΔEcut = _ natom 2Difference Metric (D) = σΔΕ natomTrust Number (T) = 1/D
24. Native conformer identificationFor a set of 30 small-to-large mutations
25. Looking forwardInsertion/deletion mutationsLoop insertion/deletionsMultiple mutationsBalloon-based protein foldingNew solvation models
26. AcknowledgmentsMichael O’DonnellBiomolecular Interaction CentreSummer Studentship Scheme, University of Canterbury