2022 DOCK tutorial 2 with PDBID 4ZUD
DOCK is a molecular modeling program capable of sampling lower-energy ligand conformations with respect to a binding surface on a given protein. DOCK utilizes and manipulates the geometry of the ligand to find the conformation that yields that most favorable interaction with the respective binding site. With this tool, millions of molecules can be rapidly screened against a target protein for the purposes of identifying new drug molecules that are physiologically relevant.
For more information on DOCK and it's uses, please refer to their online manual: DOCK6 Manual
Before beginning, create the following directories in your space so that all necessary files are organized and can be access quickly:
mkdir 001.structures 002.sphere_selection 003.gridbox 004.dock
You don't have to name your directories the same as they are named here, but be cautious since the files that will be used for this tutorial utilize this naming scheme. They will need to be changed in each file that refers to them if you don't use this naming scheme!
Be sure to have Chimera installed on your system as it will be our primary visualization and system-editing program.
Protein and Ligand Preparation
Download the 4ZUD PDB file from the RCSB PDB website and open the file in Chimera.
Select -> Open -> (pathway to pdb file on your local machine) -> Open
You will notice a few side chain residues are explicitly displayed; those are the ones that directly engage with the ligand. The structure also has some missing regions denoted by the dashed-lines. These regions do not have to be modeled to use the system for docking since the majority of the protein remains restrained during the process (except for the residues of the active site, to a certain extent). You can play around with Chimera and visualize the protein from different angles to get a complete look at the protein to ensure there are no glaring errors in the structure that could have somehow arose from the downloading and opening process (Doesn't usually happen, but it's always good to be sure before moving on!)
Many structures deposited in the PDB lack hydrogens due to the difficulty in resolving their electron densities from cryo-EM or X-ray crystallography. The structures also lack formal charges since that information is not captured with out current experimental structure-determining techniques. Both charges and hydrogens are crucial for accurately studying any chemical system, and so they both must be added manually to 4ZUD in order to prime the system for docking.
Adding Hydrogens We first want to select everything but the ligand (we will deal with the ligand in the next step). A straight forward way to only select the protein is to first select the ligand:
Select -> Residue -> OLM
And then press 'Shift left-arrow key" at the same time to invert the selection to everything but the ligand (which in this case is just the protein!)