In this tutorial, we will see how to dock libraries of ligands into proteins and rank them with AutoDock Vina Extended SAMSON Element. The AutoDock Vina Extended SAMSON Element wraps the popular protein-ligand docking program AutoDock Vina (O. Trott, A. J. Olson, AutoDock Vina: improving the speed and accuracy of docking with a new scoring function, efficient optimization and multithreading, Journal of Computational Chemistry 31 (2010) 455-461).
- SAMSON, version 0.7.0 or higher
- AutoDock Vina Extended SAMSON Element
Before starting the tutorial, please download the 2AZ8 file which contains protein-ligand complex used in this tutorial.
Launch SAMSON. Load 2AZ8.sam file provided in the archive. It will open structural models of a protein (2AZ8-A and 2AZ8-B) with a ligand (2AZ8-IA).
Let’s first add a secondary structure visual model for the protein. Select in the Document view 2AZ8-A and 2AZ8-B structural models, press Ctrl/Cmd⌘ + Shift + V (Visualization menu > Add visual model), and select the secondary structure visual model.
Note: if you cannot see the Document view, you can enable it in the Window menu, or by pressing Ctrl/Cmd⌘ + 1.
Now you can hide the 2AZ8-A and 2AZ8-B structural models by unchecking their boxes in the Document view.
Launching the AutoDock Vina Extended app
Open the AutoDock Vina Extended app by clicking on its icon . You can also find it in the App > Biology menu.
1. Setting up the system
Now we need to set up the receptor, the flexible side-chains, and the ligand.
Setup the receptor
Select the protein (2AZ8-A and 2AZ8-B) in the Document view and then press the Set receptor button.
Setup the flexible side-chains
If you want flexible side-chains, select them in the Document view or in the viewport, then press the Set flexible side-chains button. For simplicity, in this tutorial, we will not be specifying the flexible side-chains.
Setup the ligand
You can either choose to select a single link (as with the Autodock Vina SAMSON Element) by selecting the “Single ligand” radio button or choose to dock a library of ligands by selecting the “Ligand library” radio button. For the latest, you will have to provide a path to a directory containing the ligand library you want to dock. To do so, you can write this path directly in the “Set path…” line edit or click on the “Browse” button to browse to the desired directory then click on Choose. For the sake of the tutorial, we will choose to dock a library of ligands obtained from the ZINC library. Note that ZINC offers you to only download a library of molecules in a single file. You will need to split this file into files containing only one molecule and to move them to your previously specified directory.
Setup rotatable bonds
If you have set flexible side-chains or if you want to dock a single flexible ligand, you will see possible rotatable bonds in the viewport represented by green cylinders superimposed with bonds. Zoom in on the ligand (select the ligand in the Document view and then press Shift + Space).
Note: Having rotatable bonds makes the search slower but may result in more realistic docking.
You can activate or deactivate these rotatable bonds by clicking on the cylinders. They will change colors when you switch their state. Green means the bond can rotate, and red means the bond cannot rotate.
If you are docking a library of ligand like here, it is important to know that all the ligands of the library will be considered as fully flexible (meaning that all the rotatable bonds are active)
2. Setting up the search grid
The next step is to set the search grid. You can do it either by modifying the center of the grid and the size in the Element’s interface or using the delegate editor and dragging the yellow grid corners in the viewport.
3. Running the docking
Now we will set the exhaustiveness parameter and the maximum number of modes wanted:
- Set the Exhaustiveness parameter (the higher the better, but the longer the search) to 100.
- Set the Modes parameter (the maximum number of modes returned by the search algorithm) to 200.
Press the Dock library button and wait for the results.
4. Visualizing results
As soon as the computations are done, the top binding ligands are added as structural models (with the best ranked pose already displayed) and grouped in a folder called “Top ligands”. A list of conformations is also added to the Document View in order to display other poses of these ligands. You can hide all the generated structural models for the ligands by unchecking the box for this newly created folder.
To restore a conformation either double-click on the conformation in the Document view or right-click on the conformation node and in the context menu choose Restore conformation.
Note that you can also create structures from conformations, which makes it easier to see clusters of conformations. To achieve this, right-click on one or more conformations and select “Create structural models from conformations”. This will create structures for all selected poses, so you can see where clusters are. You can also click Home / Export (Ctrl / Cmd + E) to export the selection, for example as PDB files.
To export the ligand’s conformation in a separate file, restore this conformation by double-clicking on it and then select the ligand in the Top ligands folder and click the Export button in the Home > Select menu.
You can also export the docking results in a .csv format. For that, open the Results tab in the AutoDock Vina Extended Element and click on the Export results in csv file button. It will save in a file a table of ligands modes, their energies, and RMSD compared to the ligand’s best mode.
You can also plot affinity vs compounds, as can be seen in the picture below, and export this plot as an image or as in a csv file.
The plot allows you to select and restore the top conformations. By clicking in the plot on a data point corresponding to one of the top conformations, this conformation will be selected in the Document view and vice versa. By double-clicking on a data point, the conformation corresponding to it will be restored.