Difference between revisions of "DOCK Denovo Run"

Revision as of 13:01, 11 November 2016

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 look like this:

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