Flexible Docking: tarting and thin spheres

written by Stefan Gahbauer 12/30/2020

Weighted flexible docking as described in Fischer et al., Nat. Chem., 2014 [1], is implemented in DOCK3.7, however, fine-tuning docking grids using tarting or thin spheres was not possible with the common scripts used for rigid docking.

Run flexible blastermaster on protonated rec.crg.pdb including tarted residues

DOCKBASE with adapted blastermaster_flex function:

    /mnt/nfs/exc/work/stefan/Flexible_docking_Tarting_Thin_Spheres/DOCK-3.7.4-1228

This version cannot be used to protonate rec.pdb, rec.crg.pdb containing protonated flexible states must be prepared before.

You can find an example for AmpC with tarted, flexible GLN120 here:

    /mnt/nfs/exc/work/stefan/exc/Flexible_docking_Tarting_Thin_Spheres/example_AmpC

Run blastermaster for flexible grid generation:

    python /mnt/nfs/exc/work/stefan/Flexible_docking_Tarting_Thin_Spheres/DOCK-3.7.4-1228/proteins/blastermaster/blastermaster.py 
           --addNOhydrogensflag -v -f --flexiblePenaltyM=2.0 --flexibleResidues=120 
           --chargeFile="/nfs/home/stefan/exc/Flexible_docking_Tarting_Thin_Spheres/example_AmpC/amb.crg.oxt" 
           --vdwprottable="/nfs/home/stefan/exc/Flexible_docking_Tarting_Thin_Spheres/example_AmpC/prot.table.ambcrg.ambH"

This will generate INDOCK, dockfiles for flexible docking, flexible.explanation.txt and part.explanation.txt.

Thin sphere scan

After the initial grids are computed with blastermaster, thin spheres can be introduced by using the following script:

    /mnt/nfs/exc/work/stefan/Flexible_docking_Tarting_Thin_Spheres/thin_sphere_scan/new_0001_generate_ES_LD_generation_flexible.py

This script is based on the rigid-docking thin sphere scan by Reed: [2] A few new options were added for flexible thin sphere scans:

    usage: new_0001_generate_ES_LD_generation_flexible.py [-h]
    
    This is a sphere scan directory generator script. This script requires that
    you provide the full path to your original blastermaster directory that you
    want to run a sphere scan on. This looks like: python
    new_0001_generate_ES_LD_combine.py --path
    /mnt/nfs/blah/work/yourName/blah/DOCKprep/ Other options include specifying
    the: 1) DMS density (--dms) 2) electrostatic thin sphere radii (--es_rad) 3)
    ligand desolvation sphere radii (--ld_rad) 4) distance of spheres to your
    xtal-lig.pdb (--xdist) 5) Grid IDs (--flexgrids) 6) Ground state grid
    (--ground_state)
    
    optional arguments:
      -h, --help            show this help message and exit
      -p ORI_PATH, --path ORI_PATH
                            Full path of the original blastermaster directory,
                            e.g. /mnt/nfs/work/asdf/asdf/asdf/
      -d DMS, --dms DMS     DMS Density. The higher the number, the more dense the
                            molecular surface is. 10.0 is default to ensure that
                            the smaller radii spheres sufficiently cover the
                            protein surface. If your spheres have larger radii or
                            if you are using small radii for ES spheres and QNIFFT
                            fails, this value can be decreased to 1.0.
      -es ES_RAD [ES_RAD ...], --es_rad ES_RAD [ES_RAD ...]
                            Radius of Electrostatic spheres. 
                            Default is 1.0, 1.3, 1.5, 1.7, 1.9
      -ld LD_RAD [LD_RAD ...], --ld_rad LD_RAD [LD_RAD ...]
                            Radius of ligand desolvation spheres. 
                            Default is 0.1, 0.2, 0.3, 0.4, 0.5
      -xd XDIST, --xdist XDIST
                            Distance thin spheres can be from xtal-lig.pdb.
                            Default is 2 Angstroms
      -fg GNUM [GNUM ...], --flexgrids GNUM [GNUM ...]
                            Alternative conformation names. E.g. A,B,C
      -gs GROUND_STATE, --ground_state GROUND_STATE
                            Ground state conformation name. E.g. A

Example:

     python /mnt/nfs/exc/work/stefan/Flexible_docking_Tarting_Thin_Spheres/thin_sphere_scan/new_0001_generate_ES_LD_generation_flexible.py 
            -p /nfs/home/stefan/exc/Flexible_docking_Tarting_Thin_Spheres/example_AmpC 
            -d 5 -es 1.0 1.5 1.9 -ld 0.4 0.6 0.8 -xd 4 
            -fg A B C -gs A

This will take a few minutes (code is still being optimized).

Once the girds are calculated, dockfiles for different thin sphere combination need to be generated using the following script:

    /mnt/nfs/exc/work/stefan/Flexible_docking_Tarting_Thin_Spheres/thin_sphere_scan/new_0002_combine_es_ld_grids_into_combos_flexible.py

    usage: new_0002_combine_es_ld_grids_into_combos_flexible.py
      [-h] -p ORI_PATH -fg GNUM [GNUM ...] -gs GROUND_STATE
    
    This is a sphere scan directory generator script. This script requires that
    you provide the full path to your original blastermaster directory that you
    want to run a sphere scan on. This looks like: python
    new_0002_combine_ES_LD.py --path /mnt/nfs/blah/work/yourName/blah/DOCKprep/
    --flexgrids A B C --ground_state A
    
    optional arguments:
      -h, --help            show this help message and exit
      -p ORI_PATH, --path ORI_PATH
                            Full path of the original blastermaster directory,
                            e.g. /mnt/nfs/work/asdf/asdf/asdf/
      -fg GNUM [GNUM ...], --flexgrids GNUM [GNUM ...]
                            Alternative conformation names. E.g. A,B,C
      -gs GROUND_STATE, --ground_state GROUND_STATE
                            Ground state conformation name. E.g. A

Example:

    python /mnt/nfs/exc/work/stefan/Flexible_docking_Tarting_Thin_Spheres/thin_sphere_scan/new_0002_combine_es_ld_grids_into_combos_flexible.py 
           -p /nfs/home/stefan/exc/Flexible_docking_Tarting_Thin_Spheres/example_AmpC 
           -fg A B C -gs A

This will generate combo_directories containing flexible docking grids.