Joe and Brian de novo stuff
From Rizzo_Lab
This is Joe and Brian's secret wiki page for coordinating notes on the de novo project.
Contents
- 1 Version of the code on cluster that we should be using:
- 2 Current Issues:
- 3 List of features that we definitely want for the release:
- 4 List of features that would be nice to have, but not necessary for release:
- 5 List of SB2012 systems that we will use for tests:
- 6 Parameters to screen
- 7 The input file we should be using:
Version of the code on cluster that we should be using:
Joe:
/sbhome1/wjallen/work/build/dock.6.7_2015-02-17.denovo_paper/src/dock/dock6
Brian:
/sbhome1/fochtman/RCR/projects_BNL/build/dock.6.7_2015-02-17.denovo_paper.2015.10.30/bin/dock6
We will probably do a merge with dock 6.8 when that is released. Brian: If you have any edits to the code, do a diff and e-mail me the results / path to your modified code. I will merge it into my branch and confirm with you that I made that change.
Current Issues:
Working on these now:
- Joe: Update exhaustive to combine all frags into one library, just like graph / random.
- Brian: When rebuilding, do we create new torsions? What original torsions do we 'not' recreate? Why don't we recreate all?
- We no longer create new torsions but we do not create all torsions. See email attachment torenv_data_for_joe.txt
- Brian: In standard pose reproduction, how many copies of each anchor do we keep? Is this comparable to how many we are keeping in de novo?
- on average we keep 66.6 orientations per anchor / 166.5 orientations per molecule for pose reproduction
- Brian: Fixed Anchor DeNovo
- running
Not working on these right now:
- Why do some systems take so long? 1FPU? Is the timing related to or independent of hungarian / tanimoto in descriptor score?
- 1FPU only takes a long time for some coordinate sets when using hungarian in descriptor score.
- Are we still seeing differences between minimized and unminimized fragment libraries? What is the cause of this? (e.g. 1N46, 1O3D, 1O2I, 3K5V)
- Localized to hungarian score, not sure of the specific issue.
- Did we ever try standard docking with just hungarian score, and how does it affect timings? How does standard docking w/ minimized ligand affect timings?
- Yes, 95% success. Takes on average 3x as long as using grid but individual systems can take anywhere from 1x (same) to 14x (if finished...) amount of time compared to grid energy. For a smaller set I ran pose reproduction with hungarian score alone using two sets of initial coordinates (lig.am1bcc and lig.multigridmin) this data is better behaved than expected but we still saw that some systems took 40% longer for one set of coordinates than another.
- Why is the hungarian function causing descriptor score to be so slow?
- Should hungarian horizontal prune be < or <=? Should it be && or ||? What should happen if the user sets num_unmatched = 0?
- Do we want to change any of the defaults for the proposed input file?
- Why are there so many systems with 0 molecules built? Too aggressive pruning? Not enough starting anchors?
- Can we tamp down on a reasonable size for a generic library?
- Capping groups on or off for this release?
Completed:
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Are we satisfied with just using hungarian in horizontal pruning, rather than hungarian and tanimoto?-
Yep, but maybe we are still working on finding the right combination of parameters
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How long should we keep doing tests with grid score, and when should we start using multigrid score?-
we are using it now
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Joe: Does Yuchen's proposed residue number bug fix affect the de novo code?-
It seems so to me. I confirmed that it did not break anything in the de novo code. -
Scott and Dwight also confirmed that it worked, Scott referenced an earlier bug report that mentioned this same issue. -
I think Scott did / is going to commit this change.
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Joe: How many torsions should we be keeping for each fragment added? What should be the torsion rmsd cutoff?-
After some consideration, I think we should use the exact same heuristic as grow_periphery in conf_gen_ag: if (rank / rmsd > cutoff) then (prune) else (keep) -
I implemented this. By default we use the same pruning_clustering_cutoff = 100.0 (called dn_pruning_clustering_cutoff)
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Is visited flag working correctly together with max_current_ aps to control when scaffolds vs. linkers vs. sidechains can be added? -
Brian: Is scaffold_this_layer working correctly for all sampling functions?- <strike>new bool construction needs to be implemented in exhaustive
- <strike>in the process of modifying code to allow user input of this param
it was called as soon as you would try a scaffold and not after it becomes part of the ensemblefor rand and exhaustive we now only mark it if the fragment made it through the torenv check but there are cases where it will not make it through sample minimized torsions, so it is still flagged too oftenfor graph we picked a point and assumed that scaffold_this_layer was true, this has been changed so that you at least consider a scaffold, as with the other sampling functions still needs to be fixed to make sure sample_minimized_torsions actually returned a molecule
List of features that we definitely want for the release:
| Task | Owner | Complete? |
|---|---|---|
| Put molecular properties (RB, MW, etc) in mol2 header | WJA | yep |
| Put ensemble properties (RB, MW, etc) output stream at the end of each layer | WJA | yep |
| Check formal charge prune | BCF | yep |
| Combination of horizontal pruning metrics (let's consider dropping tanimoto prune and just using hungarian prune) | WJA | yep |
| Finish implementing growth trees | WJA | |
| Revisit orienting to make sure it is working as intended | WJA | yep |
| Fixed a bug where we were marking scaffold_this_layer as true for any fragment | WJA | yep |
| Update random sampling function to use last layer changes in graph function | WJA | yep |
| Do that same thing for the exhaustive function | WJA | yep |
| I don't think we ever clear the scaf_link_sid vector, we definitely should do that somewhere | WJA | yep |
| Speed up fingerprint calculations by saving reference ligand as a permanent object | xxx | |
| Speed up hungarian calculations by saving reference ligand as a permanent object | xxx | |
| Reconcile sample_minimized_torsions - maybe make it an input parameter: How many torsions to keep? | xxx | |
| When minimizing with descriptor score, make sure fingerprint is turned off | xxx |
List of features that would be nice to have, but not necessary for release:
- Add verbose flag options
- Stereo centers / volume overlap pruning
- Capping group functions (H, CH3, Halogen)
- Incorporate GA at the end of each layer
- Overhaul the simple-build function
- Monte carlo algorithm that checks bond frequency
List of SB2012 systems that we will use for tests:
For now, let's use 5-15 rotatable bonds inclusive; total = 709 systems. [Joe]: I like this set because it represents "drug-like" size molecules, and they should not be too easy / too hard.
{5RB = 107; 6RB = 96; 7RB = 103; 8RB = 75; 9RB = 66; 10RB = 75; 11RB = 57; 12RB = 41; 13RB = 38; 14RB = 26; 15RB = 25}
Parameters to screen
for DN_UNIQUE_ORIENTS in 3 6 9 ; do for DN_HEUR_UNMATCHED_NUM in 2 5 8 ; do for DN_HEUR_MATCHED_RMSD in 1.0 2.0 3.0 ; do for DN_MAX_GROW_LAYERS in 7 9 ; do for DN_MAX_CURRENT_APS in 5 7 ; do for DN_MAX_ROOT_SIZE in 50 100; do for DN_MAX_LAYER_SIZE in 50 100; do
The input file we should be using:
Note: these are currently all the defaults (except for scoring function). Once we figure out the best set of parameters for both (1) focused and (2) generic libraries, then we need to update the defaults accordingly.
conformer_search_type denovo dn_fraglib_scaffold_file fraglib_scaffold.mol2 dn_fraglib_linker_file fraglib_linker.mol2 dn_fraglib_sidechain_file fraglib_sidechain.mol2 dn_user_specified_anchor yes dn_fraglib_anchor_file fraglib_anchor.mol2 dn_use_torenv_table yes dn_torenv_table torenv_table.dat dn_sampling_method graph dn_graph_starting_points 10 dn_graph_breadth 5 dn_graph_depth 2 dn_graph_temperature 100.0 dn_pruning_conformer_score_cutoff 100.0 dn_pruning_clustering_cutoff 100.0 dn_constraint_mol_wt 1000.0 dn_constraint_rot_bon 15 dn_constraint_formal_charge 2.0 dn_constraint_charge_groups 4 dn_unique_orients 3 dn_heur_unmatched_num 5 dn_heur_matched_rmsd 2.0 dn_max_grow_layers 9 dn_max_current_aps 5 dn_max_root_size 50 dn_max_layer_size 50 dn_max_scaffolds_per_layer 1 dn_write_checkpoints yes dn_write_orients no dn_write_growth_trees no dn_output_prefix output use_internal_energy yes internal_energy_rep_exp 12 use_database_filter no orient_ligand yes automated_matching yes receptor_site_file receptor.sph max_orientations 1000 critical_points no chemical_matching no use_ligand_spheres no bump_filter no score_molecules yes contact_score_primary no contact_score_secondary no grid_score_primary no grid_score_secondary no multigrid_score_primary no multigrid_score_secondary no dock3.5_score_primary no dock3.5_score_secondary no continuous_score_primary no continuous_score_secondary no footprint_similarity_score_primary no footprint_similarity_score_secondary no ph4_score_primary no ph4_score_secondary no descriptor_score_primary yes descriptor_score_secondary no descriptor_use_grid_score yes descriptor_use_pharmacophore_score no descriptor_use_tanimoto yes descriptor_use_hungarian yes descriptor_grid_score_rep_rad_scale 1 descriptor_grid_score_vdw_scale 1 descriptor_grid_score_es_scale 1 descriptor_grid_score_grid_prefix ../003.make-grids/1ACM.rec descriptor_fingerprint_ref_filename ../001.files/1ACM.lig.multigridmin.mol2 descriptor_hungarian_ref_filename ../001.files/1ACM.lig.am1bcc.mol2 descriptor_hungarian_matching_coeff -5 descriptor_hungarian_rmsd_coeff 1 descriptor_weight_grid_score 1 descriptor_weight_fingerprint_tanimoto 0 descriptor_weight_hungarian 0 gbsa_zou_score_secondary no gbsa_hawkins_score_secondary no SASA_descriptor_score_secondary no amber_score_secondary no minimize_ligand yes minimize_anchor yes minimize_flexible_growth yes use_advanced_simplex_parameters no simplex_max_cycles 1 simplex_score_converge 0.1 simplex_cycle_converge 1.0 simplex_trans_step 1.0 simplex_rot_step 0.1 simplex_tors_step 10.0 simplex_anchor_max_iterations 500 simplex_grow_max_iterations 500 simplex_grow_tors_premin_iterations 0 simplex_random_seed 0 simplex_restraint_min no atom_model all vdw_defn_file vdw.defn flex_defn_file flex.defn flex_drive_file flex_drive.tbl
