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 /gpfs/home/guest43/scratch/denovo/trial_denovo/000.fraglib /trial_denovo/zzz.parameters/ Everything else is generated through this tutorial, prior to running the Denovo code.