ProPOSE

ProPOSE is a protein-protein docking program developped by the National Research Council (NRC) Molecular Modeling Team. Based on the direct exhaustive sampling of the translational and rotational space, ProPOSE is a deterministic alternative to common FFT-based docking methods. ProPOSE is a rigid backbone docker which allows a limited number of sidechain rearrangements relative to the input structures.

Click here for download and installation instructions.

ProPOSE has no atom typing capacity and expects proper input molecule preparation. Given the diversity of molecular systems the preparation step is not automated and requires user intervention. The "prep" directory provides some examples of preparation scripts.

ProPOSE inputs and outputs molecules in Tripos mol2 file formats. Accompanying each input mol2 file, ProPOSE requires an Amber parameters (prmtop) file. The user must insure that their molecules are fully parametrized by tleap to produce a prmtop and inpcrd file (refer to the amber manual for instructions). If cofactors, ions or non-standard aminoacids are present, they must be individually processed with antechamber and loaded in tleap (see the 1LFD example). It is recommended to add capping groups to truncated chains before running tleap (see the 3BDY example).

After successfully running tleap, the ambpdb utility program provided in the ambertools can be used to produce a Tripos mol2 file format that ProPOSE can read. Note: the input MOL2 files must contain Tripos atom types (no amber types) in the sixth column of the mol2 ATOM records.

ProPOSE TARGET=mol2 LIGAND=mol2 [options]

Available options:

   TARGET_PRM=prmtop  ::  TARGET amber prmtop filename (1)
   LIGAND_PRM=prmtop  ::  LIGAND amber prmtop filename
   TARGET_HIT=txt     ::  TARGET contact atom_id list file
   LIGAND_HIT=txt     ::  LIGAND contact atom_id list file
   TARGET_FIX=txt     ::  TARGET fixed (not repacked) atom_id list file
   LIGAND_FIX=txt     ::  LIGAND fixed (not repacked) atom_id list file
   LIGAND_RMS=mol2    ::  LIGAND structure(s) to compute output pose rmsd (2)
   EXCLUDE=mol2       ::  Molecule defining excluded volume
   EXCLUDE_PRM=prmtop ::  EXCLUDE molecule amber prmtop
   NOUT=num           ::  number of output predictions (default to 10)
   OUTLIG=mol2        ::  output ligand predictions filename (default pp_outlig.mol2)
   OUTTAR=mol2        ::  output target predictions filename (default pp_outtar.mol2)
   NUM_THREAD=num     ::  maximum number of POSIX threads (default to 12)
   LICENSE=file       ::  license file location (default $PROPOSEHOME/ProPOSE.lic)
   SROT=seed          ::  apply a random rotation of the ligand prior to docking (default 0)

Notes:

1. When the PRM file for a molecule is not given the program will look for a file with suffix ".prmtop".
2. If the LIGAND_RMS is a multimol2 file then the RMSD calculation is done on each model and the smallest value is reported. The LIGAND_RMS molecule does not need to have a prmtop file but it must have the exact same atom (id and names) as the input LIGAND molecule.

When a region on a protein is expected to be involved in the interface, docking can be restricted to this region by providing a separate file listing the atom ids defining the contact region. For example, if the amber residu mask ":1-25,35-37" defines the contact region on the ligand side then the contact region can be added using

{literal}ambmask -p ligand.prmtop -c ligand.inpcrd -prnlev 0 -out pdb -find ":1-25,35-37" \
        | awk '/ATOM/{print $2}' > ligand.hit
ProPOSE LIGAND=ligand.mol2 LIGAND_PRM=ligand.prmtop LIGAND_HIT=ligand.hit \
        TARGET=target.mol2 TARGET_PRM=target.prmtop \
        OUTLIG=ligand_docked.mol2 OUTTAR=target_docked.mol2 NOUT=10
{/literal}

Note: The atom ids provided in the LIGAND_HIT or TARGET_HIT file must be consistent with the atom ids of the respective input mol2 files. The user must consider atom and residu renumbering produced by the amber tools and modify their residu mask accordingly. Refer to the online amber manual for details on tleap residu renumbering.

In some applications the TARGET protein of interest is part of a larger complex with surrounding partners (lipid bilayer, DNA, ...). To avoid docking on TARGET systems that are too large, it is more efficient to dock on the TARGET and to group the surrounding partners using the EXCLUDE option. When this argument is used, only LIGAND poses that do not overlap with the EXCLUDE molecule are reported. Note that the interaction score with the EXCLUDE atoms are ignored.

ProPOSE does sidechain repacking of interface residues that create a clash on both the TARGET and LIGAND protein. If specific residues should not be displaced during docking they can be excluded with the LIGAND_FIX=txt and/or TARGET_FIX=txt which contain the atom_ids of the sidechain atoms.

By default ProPOSE will start 12 POSIX threads for parallel processing. On multicore computers, the execution time can be reduced by increasing this number with the argument NUM_THREAD=number on the command line. The available memory (RAM) should be ~1Gb per thread.

If you use ProPOSE in your work, please cite:

• Hogues, H., Gaudreault F., Corbeil, C. R., Deprez, C., Sulea, T., Purisima, E. O. (2018). ProPOSE: Direct Exhaustive Protein–Protein Docking with Side Chain Flexibility. Journal of Chemical Theory and Computation, 14(9), 4938-4947. [link]

Send feedback, suggestions or queries to mm-admin@nrc-cnrc.gc.ca.