John Mitchell; James McDonagh ; Neetika Nath

1. John Mitchell; James McDonagh; NeetikaNath Rob Lowe; Richard Marchese Robinson

2. RF-Score: a Machine Learning Scoring Functionfor Protein-Ligand Binding Affinities • Ballester, P.J. & Mitchell, J.B.O. (2010) Bioinformatics 26, 1169-1175

4. Calculating the affinities of protein-ligand complexes: • For docking • For post-processing docking hits • For virtual screening • For lead optimisation • For 3D QSAR • Within series of related complexes • For any general complex • Absolute (hard!) • Relative • A difficult, unsolved problem.

5. Three existing approaches … 1. Force fields

6. Three existing approaches … 2. Empirical Functions

7. Three existing approaches … 2. Empirical Functions

8. Three existing approaches … 3. Knowledge based

9. How knowledge-based scoring functions have worked … • P-L complexes from PDB • Assign atoms to types • Find histograms of type-type distances • Convert to an ‘energy’ • Add up the energies from all P-L atom pairs

12. This conversion of the histogram into an energy function uses a “reverse Boltzmann” methodology. • Thus it “assumes” that the atoms of protein and ligand are independent particles in equilibrium at temperature T. • For a variety of reasons, these are poor assumptions …

13. Molecular connectivity: atom-atom distances are miles from being independent. • Excluded volume effects. • No physical basis for assuming such an equilibrium. • Changes in structure with T are small and not like those implied by the Boltzmann distribution.

14. We thought about this … … and wrote a paper saying “It’s not true, but it sort of works”

15. We thought about this … … and wrote a paper saying “It’s not true, but it sort of works”

16. Then we had a better idea – could we dispense with the reverse Boltzmann formalism?

17. Instead of assuming a formula that relates the distance distribution to the binding free energy … • … use machine learning to learn the relationship from known structures and binding affinities.

18. Instead of assuming a formula that relates the distance distribution to the binding free energy … • … use machine learning to learn the relationship from known structures and binding affinities. • And persuade someone to pay for it!

19. Random Forest Predicted binding affinity

20. Random Forest ● Introduced by Briemann and Cutler (2001) ● Development of Decision Trees (Recursive Partitioning): ● Dataset is partitioned into consecutively smaller subsets ● Each partition is based upon the value of one descriptor ● The descriptor used at each split is selected so as to optimise splitting ● Bootstrap sample of N objects chosen from the N available objects with replacement

21.  The Random Forest is a just forest of randomly generated decision trees … … whose outputs are averaged to give the final prediction

22. Building RF-Score PDBbind 2007

23. Building RF-Score PDBbind 2007

24. Validation results: PDBbind set  Following method of Cheng et al. JCIM 49, 1079 (2009)  Independent test set PDBbind core 2007, 195 complexes from 65 clusters

25. Validation results: PDBbind set • RF-Score outperforms competitor scoring functions, at least on our test • RF-Score is available for free from our group website

26. John Mitchell; James McDonagh; NeetikaNath Rob Lowe; Richard Marchese Robinson