GAFolder and Cyclic Coordinate Descent

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.

3
(No Transcript)
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 (f, y, w 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
  structures 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

6
(No Transcript)
7
(No Transcript)
8
(No Transcript)
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.sh
tml
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 phantom 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