2020 Denovo tutorial 2 with PDBID 2GQG

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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.