DOCK 3.7 tutorial (Anat)

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DOCK 3.7

source /nfs/soft/dock/DOCK-3.7-beta3/env.csh source ~/.cshrc_dock37 (my home directory)

  • “Up directory” refers to the main directory that contains the ‘dockfiles’ and ‘working’ directories.

protein prep

blastermaster.py --addhOptions=" -HIS -FLIPs " -v '$DOCKBASE/proteins/blastermaster/blastermaster.py' use -v flag (verbose) to see what’s happening. blastermaster.py --hydrogen flags (for when you want to keep the hydrogens)

ligand prep

build_smiles_ligand.sh '$DOCKBASE/ligand/generate/build_smiles_ligand.sh' build_covalent_lib.csh '$DOCKBASE/ligand/generate/build_covalent_lib.csh' combine_gz_files.sh '$DOCKBASE/ligand/generate/combine_gz_files.sh' (make sure that there are no ^M in the smiles input file - use dos2unix [file name] command remove them).

  1. this is for running a virtual screen on a ZINC subset, thing can be in different paths.
  2. input file should contain a db2 file on each line with full path.
  3. this file may be downloaded from the zinc webpage: 'http://zinc15.docking.org/tranches/build/#'

setup_db2_zinc15_file.py '$DOCKBASE/docking/setup/setup_db2_zinc15_file.py' The commands will be: mkdir Frag ## In the top directory that also has the dockfiles and working

     directories.

cp INDOCK database_index Frag/ cd Frag/ ln -s ../dockfiles/ . setup_db2_zinc15_file.py . fragments database_index

  1. prepare databases for docking if ligand databases are all in the same directory (path).

setup_db2.csh '$DOCKBASE/docking/setup/setup_db2.csh' setup_db2_lots.py '$DOCKBASE/docking/setup/setup_db2_lots.py'

setup_db2.csh /path/to/ligands/lig_db2/

    • run it from the up directory that contains the ‘working’ and ‘dockfiles’ directory.

tip: use FULL path to the db files (and not ../../etc)

submit docking calculations

submit.csh '$DOCKBASE/docking/submit/submit.csh'

    • For small ligand libraries you prepared yourself, run it from the up directory, that now has the ‘dirlist’ file, and ‘working’ and ‘dockfiles’ directories.
    • For virtual screens of Zinc libraries - run the command from the library that has all the tranches (i.e., the ‘Frags’ library.. where you ran the setup_db2_zinc15_file.py script).

for combining docking results.

extract_all.py '$DOCKBASE/analysis/extract_all.py' getposes.py '$DOCKBASE/analysis/getposes.py' to write out more then 1 pose per molecue, use the --topx=?? flag.

    • run it from the up directory

for enrichment

enrich.py '$DOCKBASE/analysis/enrich.py' plots.py '$DOCKBASE/analysis/plots.py'

Tarting a residue in DOCK3.7

Tarting refers to the polarization of specific atoms in the protein receptor to modify (enhance/decrease) ligand preferences for specific parts of the binding site. Generally one would redefine the partial charges distribution of a specific amino acid, and then use this modified residue when calculating the electrostatic potential for the receptor. Below is a step by step example: Let's say you ran docking against RSK2, so you have a docking directory that looks like: rec.pdb, xtal-lig.pdb, dockfiles, working, INDOCK Make a new dir e.g. RSK2-tart, and copy some input files into it: mkdir RSK2-tart cp RSK2/rec.pdb RSK2/xtal-lig.pdb RSK2-tart mkdir -p RSK2-tart/working cp RSK2/working/rec.crg.pdb RSK2-tart/working cp RSK2/working/prot.table.ambcrg.ambH RSK2/working/amb.crg.oxt RSK2-tart

    • the prot.table.amb.crg.ambH and amb.crg.oxt files should be in the up directory and NOT in the ‘working’ directory.

Now edit the files to represent your tweaked polarization. Let's say we want to polarize the backbone of MET496 (In this case the kinase hinge region) by +-0.4 Edit RSK2-tart/working/rec.crg.pdb to rename "MET A 496" to "MEU A 496" Edit RSK2-tart/prot.table.ambcrg.ambH to add a MEU amino acid. You can copy the block for MET and rename it to MEU, to polarize the backbone, change the partial charge of the backbone amide proton by +0.4 (i.e. "H MEU 0.648" instead of "H MEU 0.248") lower the backbone carbonyl oxygen by the same quantity ("O MEU -0.500" to "O MEU -0.900") Edit RSK2-tart/amb.crg.oxt to reflect the same changes Now all that's left is to run the protein preparation script (blastermaster.py) with the modified parameter files, and without re-protonating the protein: blastermaster.py --addNOhydrogensflag --chargeFile=/path/to/RSK2-tart/amb.crg.oxt --vdwprottable=/path/to/RSK2-art/prot.table.ambcrg.ambH the path for the prot.table.amb.crg.ambH and amb.crg.oxt files should be in the up directory and NOT in the ‘working’ directory. When the preparation is done, your protein should be "Tarted". You can proceed to docking.

Docking with a co-factor present (waters, orthosteric ligand etc.)

Basically it’s the same as tarting. Add new entry for the co-factor in the prot.table.ambcrg.ambH and amb.crg.oxt files. Copy these two files to the up directory. Then run: blastermaster.py -v --addNOhydrogensflag --chargeFile=/path/to/modified/amb.crg.oxt --vdwprottable=/path/to/modified/prot.table.ambcrg.ambH