2012 DOCK tutorial with Streptavidin

For additional Rizzo Lab tutorials see DOCK Tutorials.

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.

Streptavidin & Biotin

Streptavidin is a tetrameric prokaryote protein that binds the co-enzyme biotin with an extremely high affinity. The streptavidin monomer is composed of eight antiparallel beta-strands which folds to give a beta barrel tertiary structure. A biotin binding-site is located at one end of each β-barrel, which has a high affinity as well as a high avidity for biotin. Four identical streptavidin monomers associate to give streptavidin’s tetrameric quaternary structure. The biotin binding-site in each barrel consists of residues from the interior of the barrel, together with a conserved Trp120 from neighbouring subunit. In this way, each subunit contributes to the binding site on the neighboring subunit, and so the tetramer can also be considered a dimer of functional dimers.

Biotin is a water soluble B-vitamin complex which is composed of an ureido (tetrahydroimidizalone) ring fused with a tetrahydrothiophene ring. It is a co-enzyme that is required in the metabolism of fatty acids and leucine. It is also involved in gluconeogenisis.

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/

The following sections in this tutorial will refer back to files within these directories.

IV. Generating Box and Grid

Box

In order to speed up docking calculations, DOCK generates a fine grid, and at each point in the grid electrostatic and a VDW probes' energies are precomputed. The energies are computed using a molecular force field. To determine the dimentions of the grid, however we first generate a box that contains the outer boundaries for grid calculation. The dimentions and location of the box can be determined using a program called showbox.

Showbox can be used interactively or a file with predetermined answers can be fed into the program.

The program asks the following questions:

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Flow Chart of Questions for Showbox (Red path is followed in this tutorial)

VII. Running DOCK in Serial and in Parallel on Seawulf

Use PBS Queue as a reference.