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Our Goals:

Our Goals:. Develop accurate computational methods for predicting structures of biological macromolecules and complexes Design new world of macromolecules with new functions: Enzymes to catalyze novel chemistry Vaccines for HIV and other diseases

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Our Goals:

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  1. Our Goals: • Develop accurate computational methods for predicting structures of biological macromolecules and complexes • Design new world of macromolecules with new functions: • Enzymes to catalyze novel chemistry • Vaccines for HIV and other diseases • Novel endonucleases for gene therapy and fighting malaria • Inhibitors of pathogen entry and function

  2. Lowest energy structures sampled on independent trajectories RMSD Energy

  3. Phil Bradley Science 2005 1ubq

  4. Extensive conformational sampling with Rosetta@Home Native (CheY)

  5. Extensive conformational sampling with Rosetta@Home Native (CheY) Lowest energy Rosetta structure Architect of Rosetta@home: David Kim

  6. “Ab initio phasing by ab initio folding” Red: PDB coordinates from crystal structure phased by selenium SAD Gray: Electron density map, phased by molecular replacement with ab initio Rosetta model Rhiju Das, Randy Read, Nature 2007

  7. Top7 X-ray structure has correct topology. Backbone RMSD to design only 1.2Å C-a Backbone Overlay Red : X-ray structure Blue : Design model Brian Kuhlman, Gautam Dantas; Science 302 1364-8

  8. Design of new protein functions • Design of new protein-protein interactions (Cholera) • Design of enzymes catalyzing novel chemical reactions • Design of new DNA cutting enzymes (Malaria) • Design of HIV vaccine

  9. Cholera toxin Designed binder Design of a cholera toxin binder Receptor-binding pocket

  10. Design proteins which cut DNA specifically within single genes in a genome • Correct mutations in human genes responsible for disease • Destroy mosquito genes needed by malaria parasite

  11. Design-WT WT-WT Redesign of endonuclease DNA cleavage specificity Justin Ashworth, Jim Havranek Nature 2006 Design-Design WT-Design

  12. Goal: Create enzymes which catalyze reactions not catalyzed by naturally occurring enzymes • Wide range of important and useful applications (synthetic chemistry, biofuels, medicine, diagnostics, etc.) • Test of our understanding of how naturally occurring enzymes work • Grand challenge for computational protein design • Success! (March 7 Science, Nature May 8)

  13. Examples of designed enzymes Daniela Roethlisberger, Andrew Wollacott

  14. Rosetta@home puts people’s computers to work to solve problems; how to enlist their brains as well? Multiplayer online computer game for solving hard problems in molecular biology, improving global health, and science education Adrien Treuille, Seth Cooper, Zoran Popovic, David Salesin

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