DOCK Denovo Run
Contents
Dock Denovo Run
The Denovo module of DOCK is a relatively new feature (as of Fall 2016) that constructs new ligand molecules inside a protein active site from a library of user-specified "fragments". These fragments are common chemical functional groups, or building blocks, that are typically selected from a ZINC library of millions of compounds based off of their frequency of appearance. These fragments are classified as scaffolds, linkers, or side chains, according to the number of atomic positions that are permitted to seed growth: 3, 2, and 1 atoms, respectively. Thus, a scaffold could seed growth on three different atoms, having three linkers bonded to each position, and a linker could seed growth on two positions, and a side-chain on one position.
Once the molecules are built within the active site, their interactions with the protein are scored using the user-specified method of scoring. This tutorial will walk through the steps needed to run a Denovo calculation on the Beta Trypsin system from the 2016 DOCK tutorial. This method will utilize the multi-grid scoring function, called through the descriptor score.
Preparing The Files
Before the Denovo module can be run, please ensure you have ran the DOCK 2016 tutorial and have all the resulting files. The tutorial can be accessed through here.
You should have these files in your directory:
001.files:
1BJU.pdb
1BJU.lig.mol2
1BJU.rec.clean.mol2
1BJU.rec.noH.mol2
selected_spheres.sph
Additionally, you will also need these parameter files:
zzz.parameters:
vdw_AMBER_parm99.defn
flex.defn
flex_drive.tbl
In order to run Denovo with multigrid scoring, we must first go through several steps:
1). Create a primary residue text file and a reference text file -- selects the primary residues of interest.
2). Make a multigrid file for each specified residue -- forms a grid for each residue specified in previous step.
3). Minimizes ligand mol2 file using multigrids from previous step.
4). Rescores ligand on multigrid to yield a minimized ligand .mol2 file. This serves as the reference ligand for Denovo calculations.
Luckily, our good friend Brian generated some extremely robust scripts to make this process easier. There is one script for each step, but we will only use the simple input files for DOCK. If you are interested in using the scripts (and a lot of debugging), they can be found on lired under: /gfps/home/guest43/scratch/denovo/trial_denovo/run/ .
DOCK Specifying Primary Residues
Create a directory within your working directory titled 008.footprint_rescore. This is where all pertinent files from this step will go, and where we will run our calculation from.
The input file for this step should be titled 1BJU.footpring_rescore.in, and should look like:
conformer_search_type rigid
use_internal_energy no
ligand_atom_file ${WORKDIR}/001.files/1BJU.lig.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 yes
footprint_similarity_score_secondary no
fps_use_footprint_reference_mol2 yes
fps_footprint_reference_mol2_filename ${WORKDIR}/001.files/1BJU.lig.mol2
fps_foot_compare_type d
fps_normalize_foot no
fps_foot_comp_all_residue no
fps_choose_foot_range_type threshold
fps_vdw_threshold 1
fps_es_threshold 0.5
fps_hb_threshold 0.5
fps_use_remainder yes
fps_receptor_filename ${WORKDIR}/001.files/1BJU.rec.clean.mol2
fps_vdw_att_exp 6
fps_vdw_rep_exp 12
fps_vdw_rep_rad_scale 1
fps_use_distance_dependent_dielectric yes
fps_dielectric 4.0
fps_vdw_fp_scale 1
fps_es_fp_scale 1
fps_hb_fp_scale 0
descriptor_score_secondary no
gbsa_zou_score_secondary no
gbsa_hawkins_score_secondary no
SASA_descriptor_score_secondary no
amber_score_secondary no
minimize_ligand no
atom_model all
vdw_defn_file ${WORKDIR}/001.files/vdw_AMBER_parm99.defn
flex_defn_file ${WORKDIR}/001.files/flex.defn
flex_drive_file ${WORKDIR}/001.files/flex_drive.tbl
ligand_outfile_prefix output
write_footprints yes
write_hbonds no
write_orientations no
num_scored_conformers 1
rank_ligands no
This calculation should be done very quickly (<10 seconds), and upon finishing you will have three output files:
1BJU.footprint_rescore.out output_footprint_scored.txt output_scored.mol2
Now, we must declare the primary residues in the active site and generate a grid file for each. Create a new file in the text editor named 1BJU.primary_residues.sh. Write this inside of it (copied from Brian's script *.fpsrescore.qsub.sh):
grep -A 1 "range_union" 1BJU.footprint_rescore.out |
grep -v "range_union" |
grep -v "\-" |
sed -e '{s/,/\n/g}' |
sed -e '{s/ //g}' |
sed '/^$/d' |
sort -n |
uniq > temp.dat
for i in `cat temp.dat`; do printf "%0*d\n" 3 $i; done > 1BJU.primary_residues.dat
for RES in `cat temp.dat`
do
grep " ${RES} " output_footprint_scored.txt |
awk -v temp=${RES} '{if ($2 == temp) print $0;}' |
awk '{print $1 " " $3 " " $4}' >> reference.txt
done
grep "remainder" output_footprint_scored.txt |
sed -e '{s/,/ /g}' |
tr -d '\n' |
awk '{print $2 " " $3 " " $6}' >> reference.txt
mv reference.txt 1BJU.reference.txt
rm temp.dat
Run the script and you should have two new files:
1BJU.primary_residues.dat 1BJU.reference.txt
These are our primary residues! Now we need to generate a grid for each one.
Generating the Grids
We must now generate a grid file for each residue. To do so, we will need the aid of another one of Brian's scripts: 1BJU.make_multigrids.qsub.sh. But before we can use his script, we need to generate two input files for Dock. Create a file named 1BJU.multigrid.in with the following inside it:
compute_grids yes grid_spacing 0.4 output_molecule yes contact_score no chemical_score no energy_score yes energy_cutoff_distance 9999 atom_model a attractive_exponent 6 repulsive_exponent 9 distance_dielectric yes dielectric_factor 4 bump_filter yes bump_overlap 0.75 receptor_file temp.mol2 box_file ../001.files/1bju.box.pdb vdw_definition_file ../001.files/vdw_AMBER_parm99.defn chemical_definition_file ../001.files/chem.defn score_grid_prefix temp.rec receptor_out_file temp.rec.grid.mol2
Create it in your 007.multigrid folder. It should possess inside it:
cd /gpfs/home/guest43/scratch/denovo/trial_denovo/009.make-mg/
export PRIMARY_RES=` cat ../008.footprint_rescore/1BJU.primary_residues.dat | sed -e 's/\n/ /g' `
export DOCKHOME="/gpfs/home/guest43/local/dock.6.7_2015-02-17.denovo_paper.2016.05.04/"
python /gpfs/home/guest43/local/dock.6.7_2015-02-17.denovo_paper.2016.05.04/bin/multigrid_fp_gen.py ../001.files/1BJU.rec.clean.mol2 1BJU.resid 1BJU.multigrid.in ${PRIMARY_RES}
rm temp.mol2 rm 1BJU.resid_*.rec.grid.mol2
/gpfs/home/guest43/local/dock.6.7_2015-02-17.denovo_paper.2016.05.04/bin/dock6 -i 1BJU.reference_multigridmin.in -o 1BJU.reference_multigridmin.out mv output_scored.mol2 1BJU.lig.multigridmin.mol2 cp 1BJU.lig.multigridmin.mol2 ../001.files/
Change the path to Dock if necessary and your primary residue file if necessary, and ensure you are using a version of Dock with the Denovo code.
After running this script, you should be given a plethora of different files. If you are still running on the 1BJU system, you should have 19 different residues: 18 individual residues, and a 19th file containing the grid for the rest of the residues. You will have four files for each residue
