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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

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Ligand configurational entropy and protein binding

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  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

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