Joe and Brian de novo stuff

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This is Joe and Brian's secret wiki page for coordinating notes on the de novo project.

Version of the code on cluster that we should be using:


We will probably do a merge after 6.8 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.

This is Brian's current version of the code for Joe to refer to:


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

Current Issue:

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

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_torsion_rmsd_cutoff                                       0.5
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_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