2020 Denovo tutorial 4 with PDBID 6UZW

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This part is a continuous toturial following the virtual screening of choosed system ([1]). All the files generated in Virtual Screen session are share with De novo session.

I. Focused De Novo Design

In this part, we will generate the same ligand present in the structure by connecting fragment from scratch. By putting the generated "ligand" back into the pocket, one could check how our simulation works in terms of the protein they interested in.

Fragment Librarie

A focused fragment library will be generate, based on original ligand molecule, in order to building the same ligand in a atomic structure.

Create a new directory for the fragment library.

mkdir 10_dn_fraglib

Create a new input file for fragment generation.

touch fragment.in

Complete the input file by answering default questions from dock and run it by calling the input file through DOCK6

dock6 -i fragment.in -o fragment.out
conformer_search_type                                        flex
write_fragment_libraries                                     yes
fragment_library_prefix                                      fraglib
fragment_library_freq_cutoff                                 1
fragment_library_sort_method                                 freq
fragment_library_trans_origin                                no
use_internal_energy                                          yes
internal_energy_rep_exp                                      12
internal_energy_cutoff                                       100.0
ligand_atom_file                                             ../01_dockprep/6UZW_lig_prepped.mol2
limit_max_ligands                                            no
skip_molecule                                                no
read_mol_solvation                                           no
calculate_rmsd                                               no
use_database_filter                                          no
orient_ligand                                                yes
automated_matching                                           yes
receptor_site_file                                           ../02_surface_spheres/selected_spheres.sph
max_orientations                                             1000
critical_points                                              no
chemical_matching                                            no
use_ligand_spheres                                           no
bump_filter                                                  no
score_molecules                                              no
atom_model                                                   all
vdw_defn_file                                           
/gpfs/projects/AMS536/zzz.programs/dock6.9_release/parameters/vdw_AMBER_parm99.defn
flex_defn_file                                               /gpfs/projects/AMS536/zzz.programs/dock6.9_release/parameters/flex.defn
flex_drive_file                                              /gpfs/projects/AMS536/zzz.programs/dock6.9_release/parameters/flex_drive.tbl
ligand_outfile_prefix                                        fragment.out
write_orientations                                           no
num_scored_conformers                                        1
rank_ligands                                                 no
                                                                  

Once fragment generation is completed, six files will be generated. (fraglib_linker.mol2, fraglib_rigid.mol2, fraglib_scaffold.mol2, fraglib_sidechain.mol2, fraglib_torenv.dat, fragment.out_scored.mol2)

By type the following command or open the mol2 file in Chimera, one can check the number of fragments generated and see how they match with the original structure file.

grep -wc MOLECULE *.mol2


Focused Denovo Growth

We will run de novo dock using fragments generated before. The fragments will connected with each other one by one with constrains such as charge and molecular weight. DOCK program will make sure the connection is reasonable before adding any single fragment.

Create a new directory for focused denovo dock.

mkdir 11_dn_focus

Create a new input file.

touch dn_focus.in

Complete the input file by answering default questions from dock and run it by calling the input file through DOCK6

dock6 -i dn_focus.in -o dn_focus.out


conformer_search_type                                        denovo
dn_fraglib_scaffold_file                                     ../10_dn_fraglib/fraglib_scaffold.mol2
dn_fraglib_linker_file                                       ../10_dn_fraglib/fraglib_linker.mol2
dn_fraglib_sidechain_file                                    ../10_dn_fraglib/fraglib_sidechain.mol2
dn_user_specified_anchor                                     no
dn_use_torenv_table                                          yes
dn_torenv_table                                              ../10_dn_fraglib/fraglib_torenv.dat
dn_sampling_method                                           graph
dn_graph_max_picks                                           30
dn_graph_breadth                                             3
dn_graph_depth                                               2
dn_graph_temperature                                         100.0
dn_pruning_conformer_score_cutoff                            100.0
dn_pruning_conformer_score_scaling_factor                    1.0
dn_pruning_clustering_cutoff                                 100.0
dn_constraint_mol_wt                                         550.0
dn_constraint_rot_bon                                        15
dn_constraint_formal_charge                                  2.0
dn_heur_unmatched_num                                        1
dn_heur_matched_rmsd                                         2.0
dn_unique_anchors                                            1
dn_max_grow_layers                                           9
dn_max_root_size                                             25
dn_max_layer_size                                            25
dn_max_current_aps                                           5
dn_max_scaffolds_per_layer                                   1
dn_write_checkpoints                                         yes
dn_write_prune_dump                                          no
dn_write_orients                                             no
dn_write_growth_trees                                        no
dn_output_prefix                                             dn_focus.out
use_internal_energy                                          yes
internal_energy_rep_exp                                      12
internal_energy_cutoff                                       100.0
use_database_filter                                          no
orient_ligand                                                yes
automated_matching                                           yes
receptor_site_file                                           ../02_surface_spheres/selected_spheres.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                                           yes
grid_score_secondary                                         no
grid_score_rep_rad_scale                                     1
grid_score_vdw_scale                                         1
grid_score_es_scale                                          1
grid_score_grid_prefix                                       ../03_gridbox/grid
multigrid_score_secondary                                    no
dock3.5_score_secondary                                      no
continuous_score_secondary                                   no
footprint_similarity_score_secondary                         no
pharmacophore_score_secondary                                no
descriptor_score_secondary                                   no
gbsa_zou_score_secondary                                     no
gbsa_hawkins_score_secondary                                 no
SASA_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                                                
/gpfs/projects/AMS536/zzz.programs/dock6.9_release/parameters/vdw_AMBER_parm99.defn
flex_defn_file                                               /gpfs/projects/AMS536/zzz.programs/dock6.9_release/parameters/flex.defn
flex_drive_file                                              /gpfs/projects/AMS536/zzz.programs/dock6.9_release/parameters/flex_drive.tbl

Focused Denovo Rescore

Create a new directory

mkdir 12_dn_focusrescore

Create an input file

touch rescore.in

Complete the input file by answering default questions from dock and run it by calling the input file through DOCK6

dock6 -i rescore.in -o rescore.out
conformer_search_type                                        rigid
use_internal_energy                                          yes
internal_energy_rep_exp                                      12
internal_energy_cutoff                                       100.0
ligand_atom_file                                             ../11_dn_focus/dn_focus.out.denovo_build.mol2
limit_max_ligands                                            no
skip_molecule                                                no
read_mol_solvation                                           no
calculate_rmsd                                               no
use_database_filter                                          no
orient_ligand                                                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
pharmacophore_score_primary                                  no
pharmacophore_score_secondary                                no
descriptor_score_primary                                     yes
descriptor_score_secondary                                   no
descriptor_use_grid_score                                    no
descriptor_use_multigrid_score                               no
descriptor_use_continuous_score                              no
descriptor_use_footprint_similarity                          yes
descriptor_use_pharmacophore_score                           yes
descriptor_use_tanimoto                                      yes
descriptor_use_hungarian                                     yes
descriptor_use_volume_overlap                                yes
descriptor_fps_score_use_footprint_reference_mol2            yes
descriptor_fps_score_footprint_reference_mol2_filename       ../04_dock/6UZW_lig_min_scored.mol2
descriptor_fps_score_foot_compare_type                       Euclidean
descriptor_fps_score_normalize_foot                          no
descriptor_fps_score_foot_comp_all_residue                   yes
descriptor_fps_score_receptor_filename                       ../01_dockprep/6UZW_rec_prepped.mol2
descriptor_fps_score_vdw_att_exp                             6
descriptor_fps_score_vdw_rep_exp                             12
descriptor_fps_score_vdw_rep_rad_scale                       1
descriptor_fps_score_use_distance_dependent_dielectric       yes
descriptor_fps_score_dielectric                              4.0
descriptor_fps_score_vdw_fp_scale                            1
descriptor_fps_score_es_fp_scale                             1
descriptor_fps_score_hb_fp_scale                             0
descriptor_fms_score_use_ref_mol2                            yes
descriptor_fms_score_ref_mol2_filename                       ../04_dock/6UZW_lig_min_scored.mol2
descriptor_fms_score_write_reference_pharmacophore_mol2      no
descriptor_fms_score_write_reference_pharmacophore_txt       no
descriptor_fms_score_write_candidate_pharmacophore           no
descriptor_fms_score_write_matched_pharmacophore             no
descriptor_fms_score_compare_type                            overlap
descriptor_fms_score_full_match                              yes
descriptor_fms_score_match_rate_weight                       5.0
descriptor_fms_score_match_dist_cutoff                       1.0
descriptor_fms_score_match_proj_cutoff                       0.7071
descriptor_fms_score_max_score                               20
descriptor_fingerprint_ref_filename                          ../04_dock/6UZW_lig_min_scored.mol2
descriptor_hms_score_ref_filename                            ../04_dock/6UZW_lig_min_scored.mol2
descriptor_hms_score_matching_coeff                          -5
descriptor_hms_score_rmsd_coeff                              1
descriptor_volume_score_reference_mol2_filename              ../04_dock/6UZW_lig_min_scored.mol2
descriptor_volume_score_overlap_compute_method               analytical
descriptor_weight_fps_score                                  1
descriptor_weight_pharmacophore_score                        1
descriptor_weight_fingerprint_tanimoto                       -1
descriptor_weight_hms_score                                  1
descriptor_weight_volume_overlap_score                       -1
gbsa_zou_score_secondary                                     no
gbsa_hawkins_score_secondary                                 no
SASA_score_secondary                                         no
amber_score_secondary                                        no
minimize_ligand                                              no
atom_model                                                   all
vdw_defn_file                                                
/gpfs/projects/AMS536/zzz.programs/dock6.9_release/parameters/vdw_AMBER_parm99.defn
flex_defn_file                                               /gpfs/projects/AMS536/zzz.programs/dock6.9_release/parameters/flex.defn
flex_drive_file                                              /gpfs/projects/AMS536/zzz.programs/dock6.9_release/parameters/flex_drive.tbl
chem_defn_file                                               /gpfs/projects/AMS536/zzz.programs/dock6.9_release/parameters/chem.defn
pharmacophore_defn_file                                       
/gpfs/projects/AMS536/zzz.programs/dock6.9_release/parameters/ph4.defn
ligand_outfile_prefix                                        descriptor.output
write_footprints                                             yes
write_hbonds                                                 yes
write_orientations                                           no
num_scored_conformers                                        1
rank_ligands                                                 no

You will have 5 files generated in this file when the process is completed. Open a file named descriptor.output_scored.mol2 in Chimera with the function "ViewDock", one can compare it with original ligand .mol2 file.

Generic Denovo Rescore

Create new Directory

mkdir 13_dn_generic_denovo

Create a input file

touch denovo.in

Complete the input file by answering default questions from dock and run it by calling the input file through DOCK6

dock6 -i denovo.in -o denovo.out


conformer_search_type                                        denovo 
dn_fraglib_scaffold_file                                     /gpfs/projects/AMS536/zzz.programs/dock6.9_release/parameters/fraglib_scaffold.mol2 
dn_fraglib_linker_file                                       /gpfs/projects/AMS536/zzz.programs/dock6.9_release/parameters/fraglib_linker.mol2
dn_fraglib_sidechain_file                                    /gpfs/projects/AMS536/zzz.programs/dock6.9_release/parameters/fraglib_sidechain.mol2
dn_user_specified_anchor                                     no
dn_use_torenv_table                                          yes
dn_torenv_table                                              /gpfs/projects/AMS536/zzz.programs/dock6.9_release/parameters/fraglib_torenv.dat
dn_sampling_method                                           graph
dn_graph_max_picks                                           30
dn_graph_breadth                                             3
dn_graph_depth                                               2
dn_graph_temperature                                         100.0
dn_pruning_conformer_score_cutoff                            100.0
dn_pruning_conformer_score_scaling_factor                    1.0
dn_pruning_clustering_cutoff                                 100.0
dn_constraint_mol_wt                                         550.0
dn_constraint_rot_bon                                        15
dn_constraint_formal_charge                                  2.0
dn_heur_unmatched_num                                        1
dn_heur_matched_rmsd                                         2.0
dn_unique_anchors                                            1
dn_max_grow_layers                                           9
dn_max_root_size                                             25
dn_max_layer_size                                            25
dn_max_current_aps                                           5
dn_max_scaffolds_per_layer                                   1
dn_write_checkpoints                                         yes
dn_write_prune_dump                                          no
dn_write_orients                                             no
dn_write_growth_trees                                        no
dn_output_prefix                                             output
use_internal_energy                                          yes
internal_energy_rep_exp                                      12
internal_energy_cutoff                                       100.0 
use_database_filter                                          no
orient_ligand                                                yes
automated_matching                                           yes
receptor_site_file                                           ../02_surface_spheres/selected_spheres.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 
pharmacophore_score_primary                                  no
pharmacophore_score_secondary                                no
descriptor_score_primary                                     yes
descriptor_score_secondary                                   no
descriptor_use_grid_score                                    yes
descriptor_use_multigrid_score                               no
descriptor_use_pharmacophore_score                           no
descriptor_use_tanimoto                                      no 
descriptor_use_hungarian                                     no
descriptor_use_volume_overlap                                no
descriptor_multigrid_score_es_euc_scale                      1.0
descriptor_weight_grid_score                            1 
gbsa_zou_score_secondary                                     no
gbsa_hawkins_score_secondary                                 no
SASA_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                                                /gpfs/projects/AMS536/zzz.programs/dock6.9_release/parameters/vdw_AMBER_parm99.defn
flex_defn_file                                               /gpfs/projects/AMS536/zzz.programs/dock6.9_release/parameters/flex.defn
flex_drive_file                                              /gpfs/projects/AMS536/zzz.programs/dock6.9_release/parameters/flex_drive.tbl