Difference between revisions of "2023 Denovo tutorial 3 with PDBID 2P16"
Stonybrook (talk | contribs) (→De Novo Design) |
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vi refinement.in | vi refinement.in | ||
| − | conformer_search_type denovo | + | conformer_search_type denovo |
| − | dn_fraglib_scaffold_file /gpfs/projects/AMS536/zzz.programs/dock6.10/parameters/fraglib_scaffold.mol2 | + | dn_fraglib_scaffold_file /gpfs/projects/AMS536/zzz.programs/dock6.10/parameters/fraglib_scaffold.mol2 |
| − | dn_fraglib_linker_file /gpfs/projects/AMS536/zzz.programs/dock6.10/parameters/fraglib_linker.mol2 | + | dn_fraglib_linker_file /gpfs/projects/AMS536/zzz.programs/dock6.10/parameters/fraglib_linker.mol2 |
| − | dn_fraglib_sidechain_file /gpfs/projects/AMS536/zzz.programs/dock6.10/parameters/fraglib_sidechain.mol2 | + | dn_fraglib_sidechain_file /gpfs/projects/AMS536/zzz.programs/dock6.10/parameters/fraglib_sidechain.mol2 |
| − | dn_user_specified_anchor yes | + | dn_user_specified_anchor yes |
| − | dn_fraglib_anchor_file 2p16_anchor.mol2 | + | dn_fraglib_anchor_file 2p16_anchor.mol2 |
| − | dn_torenv_table /gpfs/projects/AMS536/zzz.programs/dock6.10/parameters/fraglib_torenv.dat | + | dn_torenv_table /gpfs/projects/AMS536/zzz.programs/dock6.10/parameters/fraglib_torenv.dat |
| − | dn_name_identifier refine | + | dn_name_identifier refine |
| − | dn_sampling_method graph | + | dn_sampling_method graph |
| − | dn_graph_max_picks 30 | + | dn_graph_max_picks 30 |
| − | dn_graph_breadth 3 | + | dn_graph_breadth 3 |
| − | dn_graph_depth 2 | + | dn_graph_depth 2 |
| − | dn_graph_temperature 100 | + | dn_graph_temperature 100 |
| − | dn_pruning_conformer_score_cutoff 100 | + | dn_pruning_conformer_score_cutoff 100 |
| − | dn_pruning_conformer_score_scaling_factor 2 | + | dn_pruning_conformer_score_scaling_factor 2 |
| − | dn_pruning_clustering_cutoff 100 | + | dn_pruning_clustering_cutoff 100 |
| − | dn_mol_wt_cutoff_type soft | + | dn_mol_wt_cutoff_type soft |
| − | dn_upper_constraint_mol_wt 1000 | + | dn_upper_constraint_mol_wt 1000 |
| − | dn_lower_constraint_mol_wt 0.0 | + | dn_lower_constraint_mol_wt 0.0 |
| − | dn_mol_wt_std_dev 35.0 | + | dn_mol_wt_std_dev 35.0 |
| − | dn_constraint_rot_bon 15 | + | dn_constraint_rot_bon 15 |
| − | dn_constraint_formal_charge 5 | + | dn_constraint_formal_charge 5 |
| − | dn_heur_unmatched_num 1 | + | dn_heur_unmatched_num 1 |
| − | dn_heur_matched_rmsd 2.0 | + | dn_heur_matched_rmsd 2.0 |
| − | dn_unique_anchors 1 | + | dn_unique_anchors 1 |
| − | dn_max_grow_layers 1 | + | dn_max_grow_layers 1 |
| − | dn_max_root_size 25 | + | dn_max_root_size 25 |
| − | dn_max_layer_size 25 | + | dn_max_layer_size 25 |
| − | dn_max_current_aps 5 | + | dn_max_current_aps 5 |
| − | dn_max_scaffolds_per_layer 1 | + | dn_max_scaffolds_per_layer 1 |
| − | dn_write_checkpoints yes | + | dn_write_checkpoints yes |
| − | dn_write_prune_dump no | + | dn_write_prune_dump no |
| − | dn_write_orients no | + | dn_write_orients no |
| − | dn_write_growth_trees no | + | dn_write_growth_trees no |
| − | dn_output_prefix output | + | dn_output_prefix output |
| − | use_internal_energy yes | + | use_internal_energy yes |
| − | internal_energy_rep_exp 12 | + | internal_energy_rep_exp 12 |
| − | internal_energy_cutoff 100.0 | + | internal_energy_cutoff 100.0 |
| − | use_database_filter no | + | use_database_filter no |
| − | orient_ligand no | + | orient_ligand no |
| − | bump_filter no | + | bump_filter no |
| − | score_molecules yes | + | score_molecules yes |
| − | contact_score_primary no | + | contact_score_primary no |
| − | grid_score_primary yes | + | grid_score_primary yes |
| − | grid_score_rep_rad_scale 1 | + | grid_score_rep_rad_scale 1 |
| − | grid_score_vdw_scale 1 | + | grid_score_vdw_scale 1 |
| − | grid_score_es_scale 1 | + | grid_score_es_scale 1 |
| − | grid_score_grid_prefix /gpfs/projects/AMS536/2023/students/group_3_jack-abhik-jiyun/JIYCHONG/Tutorial_DOCK_VS/Rigid_dock/grid | + | grid_score_grid_prefix /gpfs/projects/AMS536/2023/students/group_3_jack-abhik-jiyun/JIYCHONG/Tutorial_DOCK_VS/Rigid_dock/grid |
| − | minimize_ligand yes | + | minimize_ligand yes |
| − | minimize_anchor no | + | minimize_anchor no |
| − | minimize_flexible_growth yes | + | minimize_flexible_growth yes |
| − | use_advanced_simplex_parameters no | + | use_advanced_simplex_parameters no |
| − | simplex_max_cycles 1 | + | simplex_max_cycles 1 |
| − | simplex_score_converge 0.1 | + | simplex_score_converge 0.1 |
| − | simplex_cycle_converge 1.0 | + | simplex_cycle_converge 1.0 |
| − | simplex_trans_step 1.0 | + | simplex_trans_step 1.0 |
| − | simplex_rot_step 0.1 | + | simplex_rot_step 0.1 |
| − | simplex_tors_step 10.0 | + | simplex_tors_step 10.0 |
| − | simplex_grow_max_iterations 250 | + | simplex_grow_max_iterations 250 |
| − | simplex_grow_tors_premin_iterations 0 | + | simplex_grow_tors_premin_iterations 0 |
| − | simplex_random_seed 0 | + | simplex_random_seed 0 |
| − | simplex_restraint_min yes | + | simplex_restraint_min yes |
| − | simplex_coefficient_restraint 10.0 | + | simplex_coefficient_restraint 10.0 |
| − | atom_model all | + | atom_model all |
| − | vdw_defn_file /gpfs/projects/AMS536/zzz.programs/dock6.10/parameters/vdw_de_novo.defn | + | vdw_defn_file /gpfs/projects/AMS536/zzz.programs/dock6.10/parameters/vdw_de_novo.defn |
| − | flex_defn_file /gpfs/projects/AMS536/zzz.programs/dock6.10/parameters/flex.defn | + | flex_defn_file /gpfs/projects/AMS536/zzz.programs/dock6.10/parameters/flex.defn |
| − | flex_drive_file /gpfs/projects/AMS536/zzz.programs/dock6.10/parameters/flex_drive.tbl | + | flex_drive_file /gpfs/projects/AMS536/zzz.programs/dock6.10/parameters/flex_drive.tbl |
Notice that this input file is pretty different from rigid.in or flex.in; different parameters have to be set for de novo. Additionally, a directory pathway to the DOCK fragment library has to be specified on top of vdw and flex parameter library; there are scaffold, linker, sidechain, and torsion environment library. | Notice that this input file is pretty different from rigid.in or flex.in; different parameters have to be set for de novo. Additionally, a directory pathway to the DOCK fragment library has to be specified on top of vdw and flex parameter library; there are scaffold, linker, sidechain, and torsion environment library. | ||
Revision as of 19:39, 26 March 2023
Introduction Denovo refinement Focused Denovo Rescoring Generic denovo
Contents
De Novo Design
As “de novo” means “from the beginning”, the de novo feature in DOCK enables designing of completely new ligands by adding new parts of a ligand for as many layers as the user wants. SAR (structure-activity relationship) study is one approach to find the relationship between the biological activity/binding affinity and the chemicals structure/characteristics of the ligand. De novo takes a similar approach; as DOCK grows different substituents and parts from the anchoring part of the ligand, it calculates the binding score, leading up to the best “combination” of the layers. This feature is especially useful when there is a known part of an existing ligand and a user wants to keep it, while wanting to explore new structures.
In this de novo tutorial we will be using the minimized ligand of 2P16, which was initially generated in the very first virtual screening tutorial. First the anchor has to be determined and prepared from the structure. This process can be done in Chimera. Open up the minimized structure (.mol2), and determine the anchor. Anchor can be determined in any way the user wants; in this tutorial we will keep the side of ligand closer to the active site and erase the rest.
The crystal reference ligand is colored in pink
.png)
The anchor is colored in red, while the rest of the ligand which will be deleted is colored in gray. The benzene ring (in red) will be the anchor, so one atom next to it has to be replaced with a dummy atom. The dummy atom will be the starting point of de novo design.
Addition of a dummy atom can be done by editing the .mol2 file.
Once you identify the atom number to replace with a dummy atom, replace the atom name with “Du”
1 C1 11.0445 45.4865 65.6128 C.ar 1 GG2 0.1391
2 C2 10.6303 46.5851 64.7323 C.ar 1 GG2 -0.1780
3 C3 9.2337 46.6594 64.2794 C.ar 1 GG2 -0.0635
4 O4 12.3967 45.4783 65.9732 O.3 1 GG2 -0.3229
5 C15 13.0206 44.4346 66.7210 C.3 1 GG2 0.1117
6 C4 8.2744 45.6305 64.7236 C.ar 1 GG2 -0.0422
7 C5 8.6936 44.5414 65.6145 C.ar 1 GG2 -0.0635
8 C6 10.0812 44.4663 66.0615 C.ar 1 GG2 -0.1780
9 Du1 6.9282 45.6680 64.2934 Du 1 GG2 0.2373
10 H2 11.3451 47.3321 64.4199 H 1 GG2 0.1515
11 H3 8.9132 47.4592 63.6282 H 1 GG2 0.1560
12 H5 7.9787 43.7993 65.9378 H 1 GG2 0.1560
13 H6 10.3993 43.6686 66.7163 H 1 GG2 0.1515
14 H151 14.0795 44.6602 66.8470 H 1 GG2 0.0480
15 H152 12.5470 44.3560 67.6996 H 1 GG2 0.0480
16 H153 12.9114 43.4902 66.1876 H 1 GG2 0.0480
In this tutorial, we will be replacing atom number 9. The xyz coordinate and charge of the atom does not need to be changed.
Once you make a change, save and visualize it on Chimera. The dummy atom should be colored in pink.
Anchor with a dummy atom”
Now you have the anchor, so transfer the mol2 file from your local computer to seawulf using scp.
First, just like other docking method, an input file needs to be created.
vi refinement.in
conformer_search_type denovo dn_fraglib_scaffold_file /gpfs/projects/AMS536/zzz.programs/dock6.10/parameters/fraglib_scaffold.mol2 dn_fraglib_linker_file /gpfs/projects/AMS536/zzz.programs/dock6.10/parameters/fraglib_linker.mol2 dn_fraglib_sidechain_file /gpfs/projects/AMS536/zzz.programs/dock6.10/parameters/fraglib_sidechain.mol2 dn_user_specified_anchor yes dn_fraglib_anchor_file 2p16_anchor.mol2 dn_torenv_table /gpfs/projects/AMS536/zzz.programs/dock6.10/parameters/fraglib_torenv.dat dn_name_identifier refine dn_sampling_method graph dn_graph_max_picks 30 dn_graph_breadth 3 dn_graph_depth 2 dn_graph_temperature 100 dn_pruning_conformer_score_cutoff 100 dn_pruning_conformer_score_scaling_factor 2 dn_pruning_clustering_cutoff 100 dn_mol_wt_cutoff_type soft dn_upper_constraint_mol_wt 1000 dn_lower_constraint_mol_wt 0.0 dn_mol_wt_std_dev 35.0 dn_constraint_rot_bon 15 dn_constraint_formal_charge 5 dn_heur_unmatched_num 1 dn_heur_matched_rmsd 2.0 dn_unique_anchors 1 dn_max_grow_layers 1 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 no bump_filter no score_molecules yes contact_score_primary no grid_score_primary yes grid_score_rep_rad_scale 1 grid_score_vdw_scale 1 grid_score_es_scale 1 grid_score_grid_prefix /gpfs/projects/AMS536/2023/students/group_3_jack-abhik-jiyun/JIYCHONG/Tutorial_DOCK_VS/Rigid_dock/grid minimize_ligand yes minimize_anchor no 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_grow_max_iterations 250 simplex_grow_tors_premin_iterations 0 simplex_random_seed 0 simplex_restraint_min yes simplex_coefficient_restraint 10.0 atom_model all vdw_defn_file /gpfs/projects/AMS536/zzz.programs/dock6.10/parameters/vdw_de_novo.defn flex_defn_file /gpfs/projects/AMS536/zzz.programs/dock6.10/parameters/flex.defn flex_drive_file /gpfs/projects/AMS536/zzz.programs/dock6.10/parameters/flex_drive.tbl
Notice that this input file is pretty different from rigid.in or flex.in; different parameters have to be set for de novo. Additionally, a directory pathway to the DOCK fragment library has to be specified on top of vdw and flex parameter library; there are scaffold, linker, sidechain, and torsion environment library.
Once you made refinement.in file, it can be processed in DOCK.
dock6 -i refinement.in -o refinement.out
Make a new directory to organize the files generated in this tutorial:
mkdir 005.denovo
Fragment Library Generation
In an input file:
vim fragment.in
Insert the following:
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/4ZUD_ligand_hydrogens.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
Run the fragment generation with the following command:
dock6 -i fragment.in -o fragment.out
