Difference between revisions of "2021 Denovo tutorial 3 with PDBID 1S19"
From Rizzo_Lab
Stonybrook (talk | contribs) (→Focused Denovo Growth) |
Stonybrook (talk | contribs) (→Focused Denovo Growth) |
||
| Line 76: | Line 76: | ||
mkdir denovo_focus | mkdir denovo_focus | ||
| + | |||
| + | Create a file called '''focus.in''' and copy the following script into the file. | ||
| + | |||
| + | conformer_search_type denovo | ||
| + | dn_fraglib_scaffold_file ../fraglib/fraglib_scaffold.mol2 | ||
| + | dn_fraglib_linker_file ../fraglib/fraglib_linker.mol2 | ||
| + | dn_fraglib_sidechain_file ../fraglib/fraglib_sidechain.mol2 | ||
| + | dn_user_specified_anchor no | ||
| + | dn_use_torenv_table yes | ||
| + | dn_torenv_table ../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 ../002.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 ../003.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=== | ===Focused Denovo Rescore=== | ||
= Generic Denovo Design with PDB 1S19 = | = Generic Denovo Design with PDB 1S19 = | ||
Revision as of 15:52, 8 March 2021
This tutorial continues where we left off from the virtual screening of 1S19, a structure of the vitamin D nuclear receptor bound to the side chain analogue calcipotriol.
Contents
Focused Denovo Design with PDB 1S19
In this section, we will generate new ligand structures using a fragment library. It will require the use of some of the output files from the Virtual Screen tutorial (found here).
Fragment Libraries
We will use a focused fragment library file based on the original ligand. To begin, we will create a new directory for this.
mkdir fraglib
Create a new file called fragment.in with the following inputs.
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 ../001_structure/1s19_ligand_dockprep.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 ../002.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
To run this, type:
dock6 -i fragment.in -o fragment.out
Once this has ran, the following files should have been generated: fraglib_linker.mol2, fraglib_rigid.mol2, fraglib_scaffold.mol2, fraglib_sidechain.mol2, fraglib_torenv.dat. To check the number of fragments in each file, you can type:
grep -wc MOLECULE *.mol2
You should get the following output upon using this command:
fraglib_linker.mol2:4 fraglib_rigid.mol2:0 fraglib_scaffold.mol2:2 fraglib_sidechain.mol2:2 fragment.out_scored.mol2:0
These fragments can also be visualized in Chimera. The results are shown below.
Focused Denovo Growth
We will be using the fragments that we have generated for the denovo dock. The different fragments will be connected together using restraints such as molecular weight and formal charges. DOCK will check the torsion environment file that was created in the fragment generation section to ensure reasonable connections are being made.
To begin, we will make a new directory and call it denovo_focus
mkdir denovo_focus
Create a file called focus.in and copy the following script into the file.
conformer_search_type denovo dn_fraglib_scaffold_file ../fraglib/fraglib_scaffold.mol2 dn_fraglib_linker_file ../fraglib/fraglib_linker.mol2 dn_fraglib_sidechain_file ../fraglib/fraglib_sidechain.mol2 dn_user_specified_anchor no dn_use_torenv_table yes dn_torenv_table ../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 ../002.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 ../003.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
