Difference between revisions of "2021 Denovo tutorial 1 with PDBID 1HW9"
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After the rescore complete, a footprint and H-bond scored txt files are generated. The descriptor scored mol2 files is also generated. | After the rescore complete, a footprint and H-bond scored txt files are generated. The descriptor scored mol2 files is also generated. | ||
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Revision as of 11:20, 22 March 2021
In this session, we are going to use the predetermined structures from the virtual screen tutorial to do de novo design
Contents
I. Focused De Novo Design
In the focused De Novo Design, we will generate the same ligand present in the structure by connecting fragments from scratch. Putting the generated fragments back into the pocket, we could check how our simulation works in terms of the protein we are interested in
Fragment Libraries
First, a focused fragment library will be generated based on the original ligand. The fragments would build the same ligand in an atomic structure.
Create a new directory for the fragment library, use the command:
mkdir 010_dn_fraglib
Create a new input file for fragment generation, use the command:
touch fragment.in
Use the following parameters to answer default questions from the dock program (vi fragment.in, and put in the parameters):
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/1HW9_ligand_with_H.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
Once the fragment.in the file is generated, run the dock6 program using the fragment.in as the input file:
dock6 -i fragment.in -o fragment.out
After the fragment library generation is complete, 6 files would be generated (fraglib_linker.mol2, fraglib_rigid.mol2, fraglib_scaffold.mol2, fraglib_sidechain.mol2, and fraglib_torenv.dat)
Using the grew command, we can check the number of fragments generated. Scp the mol2 files and open the files in Viewdock using Chimera can see how they match with the original structure file.
grep -wc MOLECULE *.mol2 | wc -l
Focused Denovo Growth
The de novo dock would be run by using fragments generated from the library. The fragments would connect with each other fragments with some constraints such as charge and molecular weight. DOCK program would make the fragments connection in an appropriate way before adding another single fragment.
Create a new directory for the fragment library, use the command:
mkdir 011_dn_focus
Create a new input file for fragment generation, use the command:
touch dn_focus.in
Use the following parameters to answer default questions from the dock program:
conformer_search_type denovo dn_fraglib_scaffold_file ../010_dn_fraglib/fraglib_scaffold.mol2 dn_fraglib_linker_file ../010_dn_fraglib/fraglib_linker.mol2 dn_fraglib_sidechain_file ../010_dn_fraglib/fraglib_sidechain.mol2 dn_user_specified_anchor no dn_use_torenv_table yes dn_torenv_table ../010_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 ../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
Once the fragment.in the file is generated, run the dock6 program using the fragment.in as the input file:
dock6 -i dn_focus.in -o dn_focus.out
After the de novo docking is complete, 8 mol2 files and 1 sh file would be generated
Focused Denovo Rescore
This step is to rescore the focused denovo growth result.
Create a new directory for the fragment library, use the command:
mkdir 012_dn_focusrescore
Create a new input file for fragment generation, use the command:
touch rescore.in
Use the following parameters to answer default questions from the dock program:
conformer_search_type rigid use_internal_energy yes internal_energy_rep_exp 12 internal_energy_cutoff 100.0 ligand_atom_file ../011.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 ../004.dock/1hw9_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 ../001.dockprep/1hw9_rec_prep.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 ../004.dock/1hw9_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 ../004.dock/1hw9_lig_min_scored.mol2 descriptor_hms_score_ref_filename ../004.dock/1hw9_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
Once the rescore.in the file is generated, run the dock6 program using the rescore.in as the input file:
dock6 -i rescore.in -o rescore.out
After the rescore complete, a footprint and H-bond scored txt files are generated. The descriptor scored mol2 files is also generated.
