SILCS-Water

Background

The SILCS-Water is a workflow that uses the SILCS-MC Docking protocol with water molecules as secondary ligands to identify the most favorable binding poses of ligands in presence of water molecules in the binding site of a protein. The water oxygen fragmaps (TIPO) are used to guide the docking of water molecules in the binding site.

SILCS-Water enables determination of the location of water molecules in the binding pocket and their impact on the predicted ligand binding orientation and affinities. The approach involves initial exhaustive MC docking of the ligand and 15 water molecules in a binding site followed by selection of a subset of waters for total LGFE calculation. In the approach, the Metropolis criteria for the MC is based on the overlap of the ligand and water with the SILCS FragMaps and the interaction energy between the waters and ligand. Results show that the SILCS-Water methodology is able to capture important waters and improve ligand positions and orientation. The workflow identifies waters interacting with ligands that occupy unfavorable locations with respect to the protein whose displacement through the appropriate ligands modifications should improve ligands binding affinity. More details of the validation study can be found in the paper [18].

SILCS-Water Using the SilcsBio CLI

Running SILCS-Water using the SilcsBio CLI basically involves running the SILCS-MC Docking/PosRef protocol with water molecules as secondary ligands by just adding the seclig=true option to the 1_run_silcsmc_* commands. The default secondary ligands are 15 water molecules. The following steps outline the process of running SILCS-Water using the SilcsBio CLI where primary ligand is sampled for refinement and the waters are docked with exhaustive sampling. Users can also refer to the SILCS-MC Docking Using the CLI for more details.

1. Launch SILCS-MC pose refinement runs with waters as secondary ligands:

   To set up and run SILCS-MC pose refinement, create a directory containing all the ligands to be evaluated. Each ligand can be stored as a separate .mol2 or .sdf file. Alternatively, all the ligands can be combined into a single .sdf file. With this information, enter the following command to set up and launch SILCS-MC refinement runs with waters as secondary ligands:

   ${SILCSBIODIR}/silcs-mc/1_run_silcsmc_local prot=<prot pdb> \
      ligdir=<directory containing ligand mol2/sdf> seclig=true
   

   Required parameters:

   • Path and name of protein PDB file:

     prot=<protein pdb file>
     

   • Path and name of directory containing ligand SDF or Mol2 files:

     ligdir=<location and name of directory containing ligand mol2/sdf>
     

     If the ligdir option is used, only one molecule per file under ligdir will be processed for SILCS-MC docking. Subdirectories under ligdir will also be processed. For an SD/SDF file containing multiple molecules, use sdfile=<path to sdfile> instead of the ligdir option.

     Warning

     Ligands, regardless of file format, must include all hydrogens, including pH-appropriate (de)protonations, and must have reasonable three dimensional conformations.

   • Perform SILCS-MC docking with secondary ligands:

     seclig=<true/false; default=false>
     

     By default, the SILCS-MC docking will be performed with the primary ligand only. Users can perform SILCS-MC docking simultaneously on multiple ligands by setting seclig=true. When set to true, 15 water molecules will be used as secondary ligands.

   For additional parameters and options:

   • Please refer to the SILCS-MC Pose Refinement Using the CLI.

2. Evaluate docked poses:

   The SILCS-MC tool set allows users to easily evaluate docked poses generated from the SILCS-MC docking runs. Users can rank order and collect the docked poses using 2_calc_lgfe_min_avg_sd (see Best-Pose Retrieval).

   For details on evaluating the resulting SILCS-MC docked poses, please refer to Assessment of SILCS-MC Docked/Refined Poses in CLI.

   Since the water molecules were used as secondary ligands in the SILCS-MC docking, a selection criteria can be applied to determine which waters to include in the total LGFE calculation. The best poses will be selected based on the total LGFE after all the SILCS-MC docking runs have been analyzed and reported in the output lgfe.csv file. The default selection criteria is for water molecules as secondary ligands and it is adopted from the SILCS-WATER paper [18].

   • Select secondary ligands based on distance cutoff:

     distcutoff=<cutoff for max distance to select seclig in Angstroms; default=4.0>
     

     The distcutoff parameter is the maximum distance allowed between the ligand and secondary ligand. By default, the distcutoff is set to 4.0 Å.

   • Select secondary ligands based on LGFE cutoff:

     lgfecutoff=<cutoff for max allowed LGFE of seclig (SLigLGFE); default=0.5>
     

     The lgfecutoff parameter is the maximum LGFE allowed for the secondary ligand. By default, the lgfecutoff is set to +0.5 kcal/mol.

   • Select secondary ligands based on total energy cutoff:

     totecutoff=<cutoff for max allowed TotE (IntE+SLigLGFE) of seclig; default=-0.6>
     

     The totecutoff parameter is the maximum total energy allowed for the secondary ligand. By default, the totecutoff is set to -0.6 kcal/mol.

   • Maximum number of runs expected in the pdb files:

     nrunsilcsmc=<max number of runs expected in the pdb files; default=1250>
     

   • Select secondary ligands based on interaction energy cutoff:

     intecutoff=<cutoff for max allowed interaction energy (IntE) between lig-seclig; default=-1.1>
     

     The intecutoff parameter is the maximum interaction energy allowed between the ligand and secondary ligand. By default, the intecutoff is set to -1.1 kcal/mol. Note that the interaction energy is the sum of the electrostatic and Lennard-Jones interaction energies between the ligand and the secondary ligand to be selected.

   • Sort the output by total LGFE:

     sortbytotlgfe=<sort lgfe.csv output by TotLGFE; true/false; default=false>
     

     When sortbytotlgfe=true, the output lgfe.csv file will be sorted by the total LGFE in ascending order. By default, the output lgfe.csv file is sorted by the ligand name in alphanumeric order.