ViewDock Tutorial

The program DOCK calculates possible binding orientations, given the structures of ligand and receptor molecules. The structure of a physiologically important target molecule can be used to find other molecules that may bind it and modulate (usually inhibit) its function. Generally, one searches a large database of commercially available compounds with DOCK, treating each as a possible "ligand," against the structure of a target protein, treated as the "receptor." Simple scoring methods are used to identify the most favorable binding modes of a given molecule, and then to rank the molecules according to these best orientations. The output consists of a large number of candidate ligands in the binding orientations considered most favorable by DOCK. It is then up to human users to look through the molecules and decide which ones are worth pursuing in the real world. Please consult the DOCK web site for more details.

ViewDock facilitates the selection of compounds by a human user from the output of DOCK (versions 3, 4 and the Northwestern University variant, "NUDock"). In this tutorial, the results of docking a small database of 30 compounds to the protein H-ras (from Protein Data Bank entry 121P) are used to illustrate the workings of ViewDock. See the ViewDock manual page for a more formal description of the program.

To follow along with the tutorial, you first need to download the files ras.pdb (the structure of the receptor, H-ras), gto.pdb (the ligand GTO bound to H-ras in the original PDB file, for comparison with docked molecules), ras.mol2 (the docked molecules output by DOCK 4, in Mol2 format), and setup.com (a file containing commands that set up the viewing context) into your working directory.

On Windows/Mac, click the chimera icon; on UNIX, start Chimera from the system prompt:

unix: chimera

A basic Chimera window should appear after a few seconds. If you like, resize it by placing the cursor on any corner and dragging with the left mouse button. Commands are entered into the Command Line and scaling and clipping operations can be performed with the Side View. One of several ways to start these tools is with Tools... Keyboard... Command Line and Tools... Viewing Parameters... Side View in the menu. Tools can be moved to a convenient location on the screen by dragging with the left or middle mouse button when the cursor is placed on the top bar.

First, open the (previously downloaded) structures of the receptor and its co-crystallized ligand. Choose File... Open. In the resulting dialog, check the option to Keep dialog up after Open. Make sure the File type is set to PDB, then locate the files. Choose ras.pdb and click Open; after that structure appears, open gto.pdb in the same way. Click Close to dismiss the dialog.

Next, start ViewDock (Tools... Docking... ViewDock); this brings up a dialog requesting the file of docked ligands (also previously downloaded). Make sure the File type is set to Dock 4 Results, then choose and open ras.mol2. The ViewDock ListBox will appear, along with a thicket of molecules in the graphics window. Move the ListBox aside if it is obstructing the graphics window or any of the other tools.

Now the receptor is in model 0, GTO is in model 1, and the docked molecules are in model 2 (the lowest available model is used for each successive structure opened, and the file of docked molecules was opened last).

In most cases, one is focusing on a particular target protein and will be viewing many different files of docked molecules; thus, many ViewDock sessions will be initiated with the same protein. It can be tedious to set up the same view over and over. One approach is to save a session with the target protein displayed as desired, and then repeatedly restart that session before opening different files of docked ligands with ViewDock. Another approach (used in this tutorial) is to put the necessary commands in a file and simply execute the command file as needed.

The command file (setup.com) used in this tutorial contains:

color aquamarine #0
chain #0@ca
disp #0 & #2 z<5
color orange #0@o=
color medium blue #0@n=
repr bs #1
color magenta #1
color byatom #2

If setup.com is in the working directory, enter the following in the Command Line (indicated here by Command:):

Command: open setup.com

Throughout the tutorial, adjust the view as desired with the mouse and Side View. Show the docked molecules as sticks to make them more prominent:

Command: repr stick #2

Command: ~disp #1

Clicking on a line chooses the corresponding compound: the line is highlighted, just the chosen compound is shown in the main graphics window, and more detailed information is shown in the lower part of the ListBox. Try clicking various lines in the ListBox to choose different docked molecules. Multiple compounds may be chosen at once. Ctrl-click adds to an existing choice rather than replacing it. To choose a block of compounds without having to hold down the mouse button, click on the first (or last) and then Shift-click on the last (or first) in the desired block.

The listing can be sorted by any column, by clicking on the header. Make sure the list is sorted by Energy score, with the most negative values (which are the most favorable) at the top. Scroll down to the lowest line in the top panel of the ListBox and click on it to choose the worst-scoring molecule. The following command can be used to locate this molecule if it is outside the view:

Command: window

There are three mutually exclusive states that can be assigned to docked compounds. Viable compounds are interesting (or have not been looked at yet), Deleted compounds are less interesting but may deserve another look, and Purged compounds are definitely not interesting. The S column shows V, D, and P to indicate these states. Viable and deleted but not purged molecules are included when File... Rewrite is used. Change the status of the worst-scoring molecule to purged by clicking the Purged checkbox near the bottom of the ListBox. Note that its listing disappears; make it reappear by checking the box next to List Purged in the Compounds menu.

Normally, a user will click on successive lines, examine the compounds in the binding site, and change the status of less interesting compounds to deleted or purged. Compounds can also be chosen by descriptor values and then changed in status collectively. Several sessions may be needed to whittle the list down sufficiently.

As an example, choose compounds based on their hydrogen-bonding interactions with the receptor. HBonds... Add Count to Entire Receptor will bring up the FindHBond tool; make sure the inter-model mode is set and increase the Line width to 3 (the detected hydrogen bonds will be shown as lines). Click OK. When the calculation is finished, new columns of descriptors will appear in the ListBox. Again, individual compounds can be examined by clicking on their respective lines in the ListBox. Use the Column menu to hide the descriptors HBond Ligand Atoms and HBond Receptor Atoms (the numbers of ligand and receptor atoms, respectively, participating in the detected ligand-receptor hydrogen bonds).

Compounds... Choose by Value opens an interface with several sections. Choose from Viable compounds and uncheck the boxes next to Description and Energy score to collapse the corresponding sections. In the HBonds (all) section, move the sliders to include 0-1 hydrogen bonds. A message near the top of the Choose by Value dialog will report that 17 of the 29 viable compounds meet the criteria. Click OK to choose the compounds and dismiss the dialog. The 17 viable compounds with 0-1 hydrogen bonds to the receptor will be chosen in the ListBox and displayed in the main Chimera window. Change these compounds to purged by clicking the Purged checkbox near the bottom of the ListBox. Uncheck the box next to List Purged in the Compounds menu to remove the purged compounds from the listing.

Finally, we will flip through the remaining listed compounds with the Movie feature. First, place a surface on the binding site (receptor residues within 7 angstroms of GTO; this may take a minute):

Command: surf #0 & :gto z<7