1. GAFolder and Cyclic Coordinate Descent Protein Structure Energy Minimization David Arndt - June 1, 2007

2. What is GAFolder? Protein structure energy minimization program Uses a Genetic Algorithm: Members of a population of candidate structures are randomly “mutated” (torsion angles are adjusted), and the best ones survive to the next generation and “mate” to combine mutations.

4. Protein quality scores GA Potential scores  Threading score (option to use Prosa)  Bump score  Hydrogen-bond count and hydrogen-bond energy  Radius of gyration  Torsion angle quality ( , ,  angles) Chemical shift correlation scores The sum of all scores is used evaluate a structure

5. Chemical shift scores ShiftX predicts chemical shifts from a candidate structure’s coordinates. We calculate the sample correlation between ShiftX-predicted chemical shifts and experimental chemical shifts. Stronger correlations indicate a better-quality structure. Score = correlation coefficient * -10 HA, HN, N, CA, CB, CO chemical shifts

9. Cyclic Coordinate Descent (CCD) CCD algorithm originally used for loop closure Iteratively adjusts torsion angles along a sub- segment of the peptide We use it for:  Closing gaps in a structure  Repairing bad torsion angles for a segment of a peptide, and using CCD to close created gaps  Aligning hydrogen bonds between Beta sheets

10. Cyclic Coordinate Descent (CCD) http://www.equinoxpharma.com/products/phragment.shtml

11. Closing gaps with CCD Green = original Blue = gap closed

12. Angle repair with CCD Green = original Blue = repaired angles

13. Angle repair on 41 Homodeller structures (Apr 17)

14. Beta sheet alignment Given list of acceptor and donor residues Align “phatom” O with real O, “phantom” H with real H

15. Example: ubiquitin (1xqq NMR)

16. Central strand dislocated

17. Alignment strategy Find segments of residues with user-specified hydrogen bonds. Gaps of 1 residue allowed. Red = anchor Green = rigid Between = flexible

18. Repaired structure Too close. PyMol creates covalent bond.

19. Hydrogens removed

20. Thanks Dr. Wishart Raj Maiti Mark Berjanskii Cam Macdonell Marie-Aude Coutouly Jack Liang Dr. David Case