2017 Denovo design tutorial 2 with PDB 4QMZ

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2017 Denovo design tutorial 2 with PDB 4QMZ

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 novel ligand molecules are scored based on a number of unique scoring algorithms/criteria specified. The fragments used 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 from 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 4QMZ system from the 2017 DOCK tutorial. This method will utilize the multi-grid scoring function, called through the descriptor score. Ensure you have all the folders and files necessary from running the 2017 tutorial. Users are encouraged to run through the traditional DOCK tutorial for the 4qmz system as many of the files are recycled for the denovo experiments. Before running the calculation, it's worth looking through the "Things to Keep in Mind" section at the bottom for some good pieces of information.

Additional Files Needed

To run the Denovo code with multigrid scoring you need these files:

    fraglib_scaffold.mol2                                                  <-- LIRed
    fraglib_linker.mol2                                                    <-- LIRed
    fraglib_sidechain.mol2                                                 <-- LIRed
    anchor_library.mol2                                                    <--LIRed
    fraglib_torenv.dat                                                     <-- LIRed
    selected_spheres.sph                                                   <-- make your own
    primary_residues_multigrid.bmp / .nrg                                  <-- make your own
    multigrid_minimized_ligand.mol2                                        <-- make your own
    vdw_AMBER_parm99.defn                                                  <--needed for regular dock
    flex.defn                                                              <--needed for regular dock
    flex_drive.tbl                                                         <-- needed for regular dock
    vdw_DumHyd.defn (needed for scoring functions other than multigrid)    <-- LIRed 

The fragment libraries and parameter files must be obtained prior to the Denovo calculation, and can be found on LIRed through the paths:


Everything else is generated through this tutorial, prior to running the Denovo code.

Preparing The Files

Before running Denovo on 4QMZ, please ensure you have gone through the DOCK 2017 tutorial and have all the resulting files. The tutorial can be accessed through here. You should have these files in your directory:


Additionally, you will also need these parameter files:


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 be titled 4qmz.footprint_rescore.in, and should look like (substitute your own directory path ~/your/own/directory/01.dockprep/4qmz.lig.mol2) :

  conformer_search_type                                        rigid
  use_internal_energy                                          no
  ligand_atom_file                                             /gpfs/home/stelehany/rizzo_rot_research/dock_tutorial/01.dockprep/4qmz.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_score_use_footprint_reference_mol2                       yes
  fps_score_footprint_reference_mol2_filename                  /gpfs/home/stelehany/rizzo_rot_research/dock_tutorial/01.dockprep/4qmz.lig.mol2
  fps_score_foot_compare_type                                  Euclidean
  fps_score_normalize_foot                                     no
  fps_score_foot_comp_all_residue                              no
  fps_score_choose_foot_range_type                             threshold
  fps_score_vdw_threshold                                      1
  fps_score_es_threshold                                       0.5
  fps_score_hb_threshold                                       0.5
  fps_score_use_remainder                                      yes
  fps_score_receptor_filename                                  /gpfs/home/stelehany/rizzo_rot_research/dock_tutorial/01.dockprep/4qmz.rec.mol2
  fps_score_vdw_att_exp                                        6
  fps_score_vdw_rep_exp                                        12
  fps_score_vdw_rep_rad_scale                                  1
  fps_score_use_distance_dependent_dielectric                  yes
  fps_score_dielectric                                         4.0
  fps_score_vdw_fp_scale                                       1
  fps_score_es_fp_scale                                        1
  fps_score_hb_fp_scale                                        0
  pharmacophore_score_secondary                                no
  descriptor_score_secondary                                   no
  gbsa_zou_score_secondary                                     no
  gbsa_hawkins_score_secondary                                 no
  SASA_score_secondary                                         no
  amber_score_secondary                                        no
  minimize_ligand                                              no
  atom_model                                                   all
  vdw_defn_file                                                /gpfs/projects/AMS536/zzz.programs/dn_dock.6.7/parameters/vdw_AMBER_parm99.defn
  flex_defn_file                                               /gpfs/projects/AMS536/zzz.programs/dn_dock.6.7/parameters/flex.defn
  flex_drive_file                                              /gpfs/projects/AMS536/zzz.programs/dn_dock.6.7/parameters/flex_drive.tbl
  ligand_outfile_prefix                                        output
  write_footprints                                             yes
  write_hbonds                                                 no
  write_orientations                                           no
  num_scored_conformers                                        1
  rank_ligands                                                 no

This calculation should be very quick (~10 seconds) and result in three output files: