1 / 15

Backbone Motion in Protein Design

Backbone Motion in Protein Design. Andrew Leaver-Fay University of North Carolina at Chapel Hill David O’Brien, Kimberly Noonan, Jack Snoeyink. Protein Design. Create an amino acid sequence that adopts a desired conformation Binds a desired small molecule Catalyses a desired reaction.

venecia-arthur
Download Presentation

Backbone Motion in Protein Design

An Image/Link below is provided (as is) to download presentation Download Policy: Content on the Website is provided to you AS IS for your information and personal use and may not be sold / licensed / shared on other websites without getting consent from its author. Content is provided to you AS IS for your information and personal use only. Download presentation by click this link. While downloading, if for some reason you are not able to download a presentation, the publisher may have deleted the file from their server. During download, if you can't get a presentation, the file might be deleted by the publisher.

E N D

Presentation Transcript

  1. Backbone Motion in Protein Design Andrew Leaver-Fay University of North Carolina at Chapel Hill David O’Brien, Kimberly Noonan, Jack Snoeyink

  2. Protein Design • Create an amino acid sequence that adopts a desired conformation • Binds a desired small molecule • Catalyses a desired reaction

  3. Dezymer From Homme Hellinga’s Lab • Use backbone of a known protein as a scaffold • Hang different sidechains from original C • Sample the sidechain conformation space • Rotamer library • Sample the ligand conformations inside binding pocket

  4. Dezymer • Combinatorial optimization • Find the best combination of rotamers to pack around the ligand of interest. • Dead End Elimination • Technique for pairwise-decomposable energy functions

  5. Why Move Backbones? • We know backbones move. Courtesy of Jane Richardson Mooers et.al. (2003) JMB 332, 741-56

  6. Why Move Backbones? • Increase power of design tools • Small motions can allow more rotamers to fit at a given location  Now search a larger sequence space. • Understand more completely the result of sequence selection on backbone motion

  7. Tools for Backbone Motion • PROBIK @ UNC • Small motions for short backbone segments • Offers • Motion Derivative Vectors • Matlab Interface

  8. Incorporating Backbone Motion • Generate Backbones Offline • Feed them into Dezymer • Goal: Incorporate motions into DEE itself

  9. Success of Dezymer • TNT Binding Protein • 2 nM Kd • R3 • Ribose Binding Protein (2dri) scaffold • Relaxed by molecular dynamics • Forces two phenylalanine rings in the binding pocket

  10. R3 – Case Study • Model of R3s structure is imperfect • Multiple Bad (>0.4 A) Overlaps • Phenylalanine rings un-stacked.

  11. R3 – Case Study • Use backbone motion to better explain R3’s success • Suggest sequence modifications for more powerful receptors

  12. R3 – PHE 190 • Small motion from 189 N-Ca-C Bond angle

  13. R3 – Preliminary Results • Dezymer result after PHE 190 BB Motion

  14. R3 – PHE 15 / PRO 237

  15. R3 – SER 215 • Ramachandran Outlier in Original Conformation

More Related