1 / 24

Ligand configurational entropy and protein binding

Ligand configurational entropy and protein binding. Chia-en A. Chang, Wei Chen, and Michael K. Gilson – PNAS(2007) Presented by Christopher Williams. Remember K*?. Uses conformational entropy of side chains to better predict redesign mutations. What about ligands?. Entropy is lost on binding

selene
Download Presentation

Ligand configurational entropy and protein binding

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. Ligand configurational entropy and protein binding Chia-en A. Chang, Wei Chen, and Michael K. Gilson – PNAS(2007) Presented by Christopher Williams

  2. Remember K*? • Uses conformational entropy of side chains to better predict redesign mutations

  3. What about ligands? • Entropy is lost on binding • How much? • What kind? • Do we care?

  4. Configurational Entropy

  5. Configurational Entropy Conformational Entropy Vibrational Entropy

  6. Configurational Entropy Conformational Entropy Vibrational Entropy

  7. Configurational Entropy Conformational Entropy Vibrational Entropy Rotation/ Translation Torsion Angle Bending Bond Stretching

  8. Higher Conformational Entropy More Wells Energy Well Higher Vibrational Entropy Wider Well

  9. How to measure entropy • S = k ln(W) • k = Boltzman constant • W = Multiplicity j

  10. The test case • Amprenavir, an HIV protease inhibitor

  11. Results • Configurational entropy loss on binding: 26.4 kcal/mol • # of accessible conformations in solution: 960 • # of accessible conformations bound: 1 • ΔS = RT ln(960) • Conformational entropy contribution: 4.1 kcal/mol

  12. Results • Configuational entropy loss on binding: 26.4 kcal/mol • Entropy loss: torsion only: 12.2 kcal/mol • Entropy loss: rotation/translation only: 15.7 kcal/mol • 12.2 + 15.7 = 27.9 != 26.7 kcal/mol

  13. Configurational Entropy Conformational Entropy Vibrational Entropy Rotation/ Translation Torsion Angle Bending There is correlation among the “separate” components of configurational entropy Bond Stretching

  14. Proof? • Similar results were returned by a separate analysis • “Quasiharmonic analysis” – essentially an MD approach • Compare 11.6 kcal/ mol to 12.3 kcal/mol • Cannot test in wetleb • Cannot yet measure separate components of entropy

  15. Predictions and Observations • Configurational entropy has a similar magnitude effect to electrostatics or hydrophobics ~25 kcal/mol • Does not include protein • Varies by ligand • Varies by tightness of binding

  16. Predictions and Observations • Vibrational entropy loss dominates • Not conformational/rotamer loss • This challenges conventional thinking • Certain atom centers are more prone to vibrational entropy • sp3 versus ring structures

  17. Applications to design • Optimizing drugs • Entropy loss inhibits binding • Rigid ligands have less entropy to lose

  18. Applications to design • Improving Scoring Functions • Current functions overweight conformational entropy, underweight vibrational • Varies by ligand

  19. Applications to design • Computational savings • Vibrational entropy dominates • May not have to enumerate every minumum

  20. Chia-en A. Chang, Wei Chen, & Michael K. Gilson. Ligand configurational entropy and protein binding. 2007 PNAS 104(5):1534-1539

  21. Questions

  22. Mining Minima Margin of Error: ± 0.8 kcal/mol

  23. q.e.d

More Related