2017 Denovo design tutorial 2 with PDB 4QMZ
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.
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:
4qmz.pdb
4qmz.lig.mol2
4qmz.rec.clean.mol2
4qmz.rec.noH.mol2
selected_spheres.sph
Additionally, you will also need these parameter files:
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/ .
