2014 DOCK tutorial with HIV Protease

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 2013, using DOCK v6.6.

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.

HIV Protease

Joe

Organizing Directories

While performing docking, it is convenient to adopt a standard directory structure / naming scheme, so that files are easy to find / identify. For this tutorial, we will use something similar to the following:

~username/AMS536/dock-tutorial/00.files/
                              /01.dockprep/
                              /02.surface-spheres/
                              /03.box-grid/
                              /04.dock/
                              /05.mini-virtual-screen/
                              /06.virtual-screen/
                             

In addition, most of the important files that are derived from the original crystal structure will be given a prefix that is the same as the PDB code, '1HVR'. The following sections in this tutorial will adhere to this directory structure / naming scheme.

II. Preparing the Receptor and Ligand

Tianao

III. Generating Receptor Surface and Spheres

Generating the Receptor Surface

Check to make sure 02.surface-spheres directory exists under dock-tutorial. If not then make the following directory:

mkdir 02.surface-sphgen
cd 02.surface-sphgen

The following steps will be carried out to generate the receptor surface using Chimera:

Open Chimera by simply typing chimera into the terminal window

| Go File -> Open and choose the PDB file of the protein containing no hydrogens (1HVR.receptor.noH.pdb) from 01.dockprep

| Further, Actions -> Surface -> Show

| Go Tools -> Structure Editing -> Write DMS in order to obtain a dms file, which we will need to place spheres

| In the new window save the surface as 1HVR.receptor.dms

Placing Spheres

We will be using SPHGEN to generate spheres: see the DOCK online owners manual for additional information:

<http://dock.compbio.ucsf.edu/DOCK_6/dock6_manual.htm>

The following steps will be used to place the spheres on the receptor surface:

1. Create a file called INSPH and fill it out as follows, then save it. This input file tells SPHGEN what to do, details of each line are below:

1HVR.receptor.dms
R
X
0.0
4.0
1.4
1HVR.receptor.sph

Input File Details: | 1HVR.receptor.dms - surface file from the previous step

| R - tells SPHGEN to place spheres either outside of the surface (R) or inside the surface (L)

| X - tells SPHGEN the subset of surface points to be used (X=all points)

| 0.0 - prevents generation of large spheres with close surface contacts(defalut=0.0)

| 4.0 - maximum sphere radius in angstroms (default=4.0)

| 1.4 - minimum sphere radius in angstroms (default=radius of probe)

| 1HVR.receptor.sph - clustered spheres file that we want to generate

IV. Generating Box and Grid

Mosavverul Arkin

1.) Make a new directory and name it: 03.box-grid/

      mkdir 03.box-grid

V. Docking a Single Molecule for Pose Reproduction

Jess Junjie Kai

VI. Virtual Screening

Virtual Screening Introduction

A virtual screen of various ligand allows for the comparison of both qualitative (e.g. position in binding site) and quantitative (e.g. energy scores) data pertaining to the each screened ligand with an originally docked molecule. Virtual screening is often used as a method to cut the cost of experimentation by narrowing down the ligands within a database and predicting which will exhibit the most favorable binding to a specific protein (with a pre-determined .grid file).

VII. Running DOCK in Parallel on Seawulf

Fengfei Lu

VIII. Frequently Encountered Problems

Joe

Write some text here..

 command or input file

Receptor surface