2018 DOCK tutorial 2 with PDBID 1C87

For additional Rizzo Lab tutorials see DOCK Tutorials. Use this link Wiki Formatting as a reference for editing the wiki. This tutorial was developed collaboratively by the AMS 536 class of 2018, using DOCK v6.8 and it shows how to dock a ligand into a receptor.

I. Introduction

DOCK

DOCK is a molecular docking program used in drug discovery. It was developed by Irwin D. Kuntz, Jr. and colleagues at UCSF (see UCSF DOCK). This program, given a protein binding site and a small molecule, tries to predict the correct binding mode of the small molecule in the binding site, and the associated binding energy. Small molecules with highly favorable binding energies could be new drug leads. This makes DOCK a valuable drug discovery tool. DOCK is typically used to screen massive libraries of millions of compounds against a protein to isolate potential drug leads. These leads are then further studied, and could eventually result in a new, marketable drug. DOCK works well as a screening procedure for generating leads, but is not currently as useful for optimization of those leads.

DOCK 6 uses an incremental construction algorithm called anchor and grow. It is described by a three-step process:

1. Rigid portion of ligand (anchor) is docked by geometric methods.
2. Non-rigid segments added in layers; energy minimized.
3. The resulting configurations are 'pruned' and energy re-minimized, yielding the docked configurations.

1C87

In this tutorial we will use PDB code 1C87, which is the crystal structure of protein tyrosine phosphatase 1B complexed with 2-(oxalyl-amino-4,7-dihydro-5H-thieno[2,3-C]pyran-3-carboxylic acid.

Organizing Directories

We are going to create and organize directories so it would be easier for us to find or identify files in each directory.

~/gpfs/projects/AMS536/2018/ /001.files/ /002.spheres/ /003.box/ /04.dock/ /05.large-virtual-screen/ /06.virtual-screen/ /07.footprint/ /08.print_fps

II. Preparing the Receptor and Ligand

Download the PDB File (1C87)

We are going to the PDB website (https://www.rcsb.org/) to download 1C87.pdb file and transfer this pdb file to your directory. First, open Chimera and load 1C87.pdb file. Remove the receptor and save ligand (not HOH) in mol2.format. "mol" format shows types of bonds whether it is single or double bond. Then, add H on receptor and ligand by clicking Tools and Structure Editing and save the files. (NOTE: when you add H on ligand, make the charge -1. Check the article that is related to pdb file to decide whether it should be pronated or depronated.) Lastly, open the receptor file and click Surface Editing and write DMS file. Make sure to save all files. So far, we will have these files ready.

1c87.pdb lig_withH_charge_1c87.mol2 noh_receptor_1c87.mol2 lig_withH_1c87.mol2 noh_lig_1c87.mol2 rec_withH_1c87.mol2

After saving these two files with H, transfer files into 001.files directory:

 scp -r ./*1c87* username@login.seawulf.stonybrook.edu:/gpfs/projects/AMS536/2018/your_directory_name/001.files

III. Generating Receptor Surface and Spheres

Generating the Receptor Surface

Make sure sphere directory is created and open the directory:

  mkdir 002.surface
  cd 002.surface

Open Chimera and load the receptor surface:

Open Chimera in the terminal to view the receptor (noh_receptor_1c87.mol2) file, which is located in the 001.files directory. Go to Action -> Surface -> Show and it will show the surface receptor. Next, save a DMS file as noh_surface_rec.dms by clicking Tools -> Structure editing -> Write DMS.

Creating Spheres We are going to create spheres by using the Sphgen program.

1. Create an input file

vi INSPH 

 Copy this script in INSPH input file.
 ./noh_surface_rec.dms
 R
 X
 0.0
 4.0
 1.4
 1c87.spheres.sph

The first line ./noh_surface_rec.dms specifies the input file. R means that spheres generated will be outside of the receptor surface. X specifies all the points will be used. 0.0 is the distance in angstrom and it will avoid steric clashes. 4.0 is the maximum surface radius of the spheres and 1.4 is the minimum radius in angstroms.The last line 1c87.spheres.sph creates the file that has clustered spheres.

2. Run the Sphgen program

 sphgen -i INSPH -o OUTSPH

3. Open Chimera to visualize the generated spheres Load 1c87.recep.sph file.

File:Generated 1C87 surface spheres.png

The generated 1C87 surface spheres