Andrew Leaver-Fay, PhD Baker Lab University of Washington

1. Andrew Leaver-Fay, PhD Baker Lab University of Washington

2. mini

5. Speed. Flexibility. Usability. O(N2) Past O(N) & O(Nlg N) Present O(k) Future

6. Speed. Flexibility. Usability.

7. Speed. Flexibility. Usability.

8. Speed. Flexibility. Usability.

9. Speed. Flexibility. Usability. O(N2) Past O(N) & O(Nlg N) Present O(k) Future

10. Model Protocol Pose pose; ScoreFunction * sfxn; Mover * mover; … MonteCarlo MC( sfxn ); … for i = 1 to X mover->apply( pose ); MC.boltzman( pose ); // 1 sfxn call, 1 pose copy

11. Model Protocol Pose pose; ScoreFunctionOP sfxn; MoverOP mover; … MonteCarlo MC( sfxn ); … for i = 1 to X mover->apply( pose ); MC.boltzman( pose ); // 1 sfxn call, 1 pose copy

12. a b a b O(N2)  O(NlgN) Scoring • Neighbor detection: O(N2)  O(N lg N) • NxN tables  sparse graph • Score terms left to themselves ScoreFunction evaluates terms for neighboring residue pairs* • O(N2) terms replaced with O(N) equivalents O(NlgN) O(N) O(N + k) O(N)

13. EnergyMethod Hierarchy Count Range Context Dependcy

14. Scoring Real ScoreFunction::operator()( Pose & pose ) const pose.update_residue_neighbors( info_ ); setup_for_scoring( pose ); for e = {u,v } pose.energy_graph() eval_cd_2b( pose.res(u), pose.res(v) ); if ( pose.moved_relative( u, v ) ) total += eval_ci_2b( pose.res(u), pose.res(v), e); else total += e; total += eval_cd_1b( pose ); total += eval_ci_1b( pose ); finalize( total ); return total;

15. ScoreFunction as a Container • Holds EnergyMethods that the user wants evaluated • Input to • minimizer • pack_rotamers • rotamer_trials

17. ScoreFunction as a Container • Holds EnergyMethods that the user wants evaluated • Input to • minimizer • pack_rotamers • rotamer_trials

18. ScoreFunction as a Container • Holds EnergyMethods that the user wants evaluated • Input to • minimizer • pack_rotamers • rotamer_trials • OnTheFlyInteractionGraph • GreenPacker

19. GreenPacker Reuses RPEs for groups of residues that aren’t moving wrt each other. For Example: Fixed-backbone ligand docking Fixed backbone protein docking

20. GreenPacker Reuses RPEs for groups of residues that aren’t moving wrt each other. Prot/Prot CI 2B energies reused Prot/Prot CI 2B energies reused Prot/Prot CD 2B energies freshlycalculated Prot/Prot CD 2B energies freshlycalculated All Prot/Prot 2B energies freshly calculated

21. GreenPacker Reuses RPEs for groups of residues that aren’t moving wrt each other. Prot/Prot CI 2B energies reused Prot/Prot CI 2B energies reused Prot/Prot CD 2B energies freshlycalculated Prot/Prot CD 2B energies freshlycalculated All Prot/Prot 2B energies freshly calculated

22. GreenPacker Reuses RPEs for groups of residues that aren’t moving wrt each other.

23. GreenPacker Reuses RPEs for groups of residues that aren’t moving wrt each other.

24. GreenPacker Reuses RPEs for groups of residues that aren’t moving wrt each other.

25. GreenPacker • User identifies residue groups that remain fixed wrt each other • 1st packing: • save rotamer internal geometry • save CI 2B energies • Subsequent packings: • Find correspondence between original rotamers and new rotamers based on internal geometry • Intra-group: • Reuse saved CI 2B energies for rotamers that have a correspondence • Compute fresh CI 2B energies for those that don’t • Compute CD 2B energies • Inter-group: • Compute all 2B energies

27. ScoreFunction as a Container • Holds EnergyMethods that the user wants evaluated • Input to • minimizer • pack_rotamers • rotamer_trials • OnTheFlyInteractionGraph • GreenPacker

28. ScoreFunction as a Container • Holds EnergyMethods that the user wants evaluated • Input to • minimizer • pack_rotamers • rotamer_trials • OnTheFlyInteractionGraph • GreenPacker • Enzyme Multi State Interaction Graph* • LoopScoreFunction* • LoopPacker* • Sidechain Minimizer*

29. Minimization • update_domain_map: O(N) • setup_for_derivatives: O(N) • set_DOF + refold: O(N) • eval_atom_derivative: O(k) -- (Phil?) • score: O(N + k) Efficient to minimize all residues, inefficient to minimize one residue

30. Output Sensitive Refold Problem: after m updates to the DOFs of an atom tree, refold. k = # atoms that move O(N+m): refold from root O(m2+k) (complicated) O(k+m): DFS -- Snoeyink set_chi

31. Output Sensitive Refold DFS: Record each atom with a DOF change -- O(m) Mark each atom with a DOF change as “unreached” Start a DFS from each unvisited atom, stopping at atoms that have already been visited in the DFS. Mark reached atoms -- O(k) Refold from unreached atoms with DOF changes

32. Output Sensitive Refold DFS: Record each atom with a DOF change -- O(m) Mark each atom with a DOF change as “unreached” Start a DFS from each unvisited atom, stopping at atoms that have already been visited in the DFS. Mark reached atoms -- O(k) Refold from unreached atoms with DOF changes

33. Output Sensitive Refold DFS: Record each atom with a DOF change -- O(m) Mark each atom with a DOF change as “unreached” Start a DFS from each unvisited atom, stopping at atoms that have already been visited in the DFS. Mark reached atoms -- O(k) Refold from unreached atoms with DOF changes

34. Output Sensitive Refold DFS: Record each atom with a DOF change -- O(m) Mark each atom with a DOF change as “unreached” Start a DFS from each unvisited atom, stopping at atoms that have already been visited in the DFS. Mark reached atoms -- O(k) Refold from unreached atoms with DOF changes

35. Loop Modeling Example Step 33 Step 34

36. O(k) minimization • “Sidechain minimizer” • Rotamer trials w/ minimization • Pre-minimize rotamers • Pre-minimize rotamer pairs* • Without modifying core::pack! • class RotamerOperation • class RotamerSetOperation

37. When is mini done? • R++ functionality  mini functionality • Release?

38. Plug for Roland Dunbrack’s Talk Tomorrow -0.2 0 0.4

39. Acknowledgements Mini Community David Baker Brian Kuhlman Jeff Gray