2020 Denovo tutorial 2 with PDBID 2GQG
From Rizzo_Lab
Contents
I. Focused Growth
First, we will attempt to rebuild the original ligand from a small fragment library generated from only the original ligand itself.
Fragment Library
In a new directory for fragment library creation, create an input file for the dock6 fragment library generation program:
mkdir fraglib cd fraglib touch fraglib.in
Either pre-fill the .in file with the following lines or answer the prompts when running dock6. Make sure to update the ligand .mol2 path and selected_spheres path to fit your directories.
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/2GQG_lig_wH.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 output write_orientations no num_scored_conformers 1 rank_ligands no
To create the fragment library, run dock6:
dock6 -i fraglib.in
denovo growth using a focused library
Make a new directory for the growth steps, and make an input file for the denovo growth:
mkdir denovo cd denovo touch denovo.in
As always, run dock6 using the input file and answer the prompts accordingly (or pre-fill the .in file):
dock6 -i denovo.in
You may want to submit this job to seawulf using a SLURM script, as it can take some time.
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 2 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 yes dn_output_prefix 2gqg.final 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.boxgrid/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
Transfer the resulting output files to your local machine and examine the results in chimera, as done previously for flexible docking. There should be many ligand structures generated, at least one of which should match the original ligand and be docked appropriately.
II. Generic Growth using a single grid
For the simplest way to do de novo growth using a generic library, the only difference from the focused growth is the fragment library. In this case, the fragment library to use already exists in the DOCK parameters directory.
Make a new directory and input file for generic growth:
mkdir denovo-generic cd denovo-generic touch denovo.in
Fill the denovo.in file with the following lines, making sure to update the paths for your directory layout.
conformer_search_type denovo
dn_fraglib_scaffold_file ${DOCKHOME}/parameters/fraglib_scaffold.mol2
dn_fraglib_linker_file ${DOCKHOME}/parameters/fraglib_linker.mol2
dn_fraglib_sidechain_file ${DOCKHOME}/parameters/fraglib_sidechain.mol2
dn_user_specified_anchor no
dn_use_torenv_table yes
dn_torenv_table 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 4
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.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_pharmacophore_score no
descriptor_use_tanimoto no
descriptor_use_hungarian no
descriptor_use_volume_overlap 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 grid
descriptor_volume_score_reference_mol2_filename descriptor_volume_score_reference.mol2
descriptor_volume_score_overlap_compute_method analytical
descriptor_weight_grid_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 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 ${DOCKHOME}/parameters/vdw_AMBER_parm99.defn
flex_defn_file ${DOCKHOME}/parameters/flex.defn
flex_drive_file ${DOCKHOME}/parameters/flex_drive.tbl
chem_defn_file chem.defn
Note that I previously exported $DOCKHOME as /gpfs/projects/AMS536/zzz.programs/dock6.9_release in my .bashrc ; Use the complete path in your file if you do not have this shortcut. This job must be submitted to the seawulf using a SLURM script:
vim dn-job.sh
#!/bin/bash #SBATCH --partition=long-40core #SBATCH --time=48:00:00 #SBATCH --nodes=1 #SBATCH --ntasks=1 #SBATCH --job-name=dn-generic #SBATCH --output=%x-%j.o echo "============================= SLURM JOB =================================" date echo echo " The job will be started on the following node(s):" echo $SLURM_JOB_NODELIST echo echo "Slurm user: $SLURM_JOB_USER" echo "Run directory: $(pwd)" echo "Job ID: $SLURM_JOB_ID" echo "Job name: $SLURM_JOB_NAME" echo "Partition: $SLURM_JOB_PARTITION" echo "Number of nodes: $SLURM_JOB_NUM_NODES" echo "Number of tasks: $SLURM_NTASKS" echo "Submitted from: $SLURM_SUBMIT_HOST:$SLURM_SUBMIT_DIR" echo "=========================================================================" date echo "Starting DOCK6.9 Simulation" dock6 -i denovo.in -o denovo.out echo "Generic de novo growth done" date
And submit your job to the queue:
sbatch ./dn-job.sh
After the seawulf has finished or terminated the job, transfer the output file rescore.out_scored.mol2 and examine the results in chimera, as for flexible docking and focused growth.
