2013 DOCK tutorial with Orotodine Monophosphate Decarboxylase

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.

Orotodine Monophosphate Decarboxylase

The protein receptor which is the subject of this tutorial is orotodine monophosphate decarboxylase (OMP), a homodimeric protein from the organism Methanobacterium thermoautotrophicum. OMP is involved in the biosynthesis of several pyrimidines including uridine monophosphate (UMP), the ligand used in this tutorial. UMP is a pyrimidine-based nucleotide monomer of RNA. The structure used for this tutorial can be found at the Protein Data Bank under accenssion number 1LOQ.

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.original-files/
                              /01.dockprep/
                              /02.surface-spheres/
                              /03.box-grid/
                              /04.dock/
                              /05.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, '1LOQ'. The following sections in this tutorial will adhere to this directory structure / naming scheme.

II. Preparing the Receptor and Ligand

Ye and Xing

III. Generating Receptor Surface and Spheres

Nick and Artem

IV. Generating Box and Grid

Yuan and Jiahui

V. Docking a Single Molecule for Pose Reproduction

Jiaye, He, and Natalie

VI. Virtual Screening

Brian and Koushik

VII. Running DOCK in Serial and in Parallel on Seawulf

The SeawulfCluster is a 470-processor Linux Cluster capable of highly parallel processing. This parallel processing allows dock virtual screens to be compelted in a fraction of the time as a signle processor.

If you are docking multiple ligands, you can use more than processor in parallel mode, but you should never use more processors than you have ligands.

Running DOCK in Serial on a Single processor

Before we can run DOCK on seawulf we need to copy the proper files from herbie to seawulf