The window pictured below. Note that the GUI version is limited to only 7 different probe types. If you would like to use more than 7 different types of probes, please use the non-GUI interface for DruGUI 2.0.
This window presents all the options available to users for setting up a druggability simulation. Users can click the '?' button for an explanation of each selection option. Below, we will describe the sections in detail.
These are the PSF and PDB files we mentioned above. Provide the full path to these files, or use the 'Browse' button to search for them in a file explorer (recommended).
See the 'Probe set' section below for the definition of the 7 core probes. This will be a good option for most users. If you would like to use probes different from those 7 core ones in your druggability simulations, check the box for 'Different probes'.
This is where you can specify the probes you would like to add to your simulation box, along with the number of each. If using different probes, see the probe list below for their short names and add them in the name box.
Here, you can define the simulation box padding and box boundary. If your system has a membrane, check the 'Embedded in a bilayer membrane' checkbox.
This is where you will specify the paths to the CHARMM RTF and PRM you downloded earlier. Use the 'Browse' button to identify them using a file explorer (recommended).
Here, define the location where the output folder will be created (the current directory from where you ran the DruGUI() command is a good choice and give that folder a name. Define the number of simulation replicates that will be created (4 is a good starting point) and specify the length of each simulation. In the 'Additional parameters' box, specify the path to other CHARMM PRM files that are needed for your system. For instance, if you chose to add a membrane, make sure you select the lipid PRM file. At the bottom, specify the path to you VMD executable.
Once you are satisfied with your choices and double checked that your paths are correct, click 'Prepare System' to run DruGUI. You can see the code output in your terminal to confirm that everything is working. Once it finishes, exit the Python session and check the folder that was created (in this example, the 'md' folder). There should be individual simulation folders inside of the defined output folder, one for each druggability simulation that was prepared.
Now, run the simulations that the GUI window prepared with NAMD. If you receive any force field errors, go back and check the 'Additional parameters' section in the setup window.
After completing each druggability simulation, you will have a sim.dcd file containing your trajectorty. This trajectory can be analyzed to determine the druggable sites of your system. Return to the DruGUI 2.0 window and notice the dropdown box at the very top. Click here and switch from 'Prepare System' to 'Analysis Results'. This will show the following window:
Switch to the Analysis Result section in the GUI. Add the appropriate files from your completed druggability simulation. This section allows you to access the druggability of your protein of interest. If your protein is druggable you can check to see how a ligand overlaps with the probes making up the druggable site. To evaluate the site, first access the druggability of the system, then once protein_heavyatoms.pdb is generated overlap the ligand onto this PDB file. Then you can evaluate how well a ligand overlaps with a druggable site.
This window presents all the options available to users for analyzing a druggability simulation. Users can click the '?' button for an explanation of each selection option. Below, we will describe the sections in detail.
In this section, specify the paths to the same PSF and PDB files that you used to setup your druggability simulation. Specify the probes used in setup (unless you only want to analyze a subset, but it is recommended to use all the same probes) and specify the protein selection that you want to analyze for druggability (heavy atom selection is recommended). And finally, specify the path to the output dcd file from your simulation. If you ran multiple replicates, you can load all of them in for a combined analysis.
Here, you can change how the druggability "grid" is constructed to assess druggable sites. It is recommended for most users to keep the defaults.
Specify the path to your working directory and give a name to where the output analysis files will be placed (here, dg).
This section has a lot of parameters that are of central importance to how druggability is assessed. However, we recommend users stick to the defaults, which are reasonable and should work well for most cases.
Then, to run the full druggability analysis, click the 'Access Druggability' button and monitor the terminal output. The resulting analysis files will be written to the provided folder in the provided path.
The next section is for if you want to compare an existing ligand to the druggable sites you found in the previous section.
Here, specify the paths to the ligand PDB that you want to compare against your druggable site(s), and also the path to the DSO output file from the previous analysis step.
We recommend keeping the defaults here, but feel free to adjust the Maximum dG depending on your specific protein and ligand.
Once you have those options filled out, click the 'Evaluate Site' button to perform the remaining analysis.
One of the major improvements introduced in DruGUI 2.0 is the ability to perform all GUI-related operations (like those described above) within a Python API. To do this, prepare the same files and paths that you would if using the GUI window, but specify them within the following function in a Python session or script. The drugui_prepare function can be loaded and executed as follows.
from prody import *
from prody.drugui import drugui_prepare
drugui_prepare(psf="/Users/carlosventura/tutorial_files/mdm2.psf",
pdb="/Users/carlosventura/tutorial_files/mdm2.pdb",
prefix="md",
outdir_location="/Users/carlosventura/tutorial_files/",
vmd='/Applications/VMD1.9.4a57-arm64-Rev12.app/Contents/vmd/vmd_MACOSXARM64',
cgenff_rtf='/Users/carlosventura/tutorial_files/top_all36_cgenff.rtf',
cgenff_parm="/Users/carlosventura/tutorial_files/par_all36_cgenff.prm",
additional_parameters=["/Users/carlosventura/tutorial_files/par_all36_cgenff.prm",
"/Users/carlosventura/tutorial_files/par_all27_prot_lipid_na.inp",
"/Users/carlosventura/tutorial_files/par_all36_carb.prm",
"/Users/carlosventura/tutorial_files/par_all36_lipid.prm",
"/Users/carlosventura/tutorial_files/par_all36_na.prm",
"/Users/carlosventura/tutorial_files/par_all36_prot.prm",
"/Users/carlosventura/tutorial_files/toppar_water_ions.str"],
Probes=True,
probes_and_percent={"IPRO": 16, "IMID": 14, "ACTT": 14, "ACAM": 14, "IPAM": 14, "IBTN": 14, "BENZ": 14},
solvent_padding=15,
boundary_padding=2.4,
neutralize=True,
lipids=False,
write_conf=True,
n_sims=4,
sim_length=40,
constrain="heavy")
And, similarly, the analysis functions can be accessed with the drugui_analysis function as follows within the same Python session.
from prody.drugui import drugui_analysis
from prody.drugui import drugui_evaluate
drugui_analysis(pdb='/Users/carlosventura/tutorial_files/md.pdb',
psf='/Users/carlosventura/tutorial_files/md.psf',
dcds = '/Users/carlosventura/tutorial_files/sim.dcd',
prefix = 'dg',
outdir_location = '/Users/carlosventura/tutorial_files/',
selection = "noh and protein",
grid_spacing = 0.5,
contact_distance = 4.0,
align = 'calpha',
temperature = 300.,
merge_radius = 5.6,
n_frames = 1,
n_probes = 7,
delta_g = -1.0,
min_n_probes = 6,
low_affinity = 10,
max_charge = 2,
n_solutions = 3,
n_charged = 3,
probes = ['IPAM', 'IPRO', 'ACTT', 'IBUT', 'ACAM', 'IMID', 'BENZ'])
drugui_evaluate(prefix="dg",
dso="/Users/carlosventura/tutorial_files/dg.dso.gz",
pdb="/Users/carlosventura/tutorial_files/ligand.pdb",
outdir_location="/Users/carlosventura/tutorial_files/",
radius=1.5,
delta_g=-1.0)
There are 129 available probes in DruGUI 2.0. Theyare characterized as (A) core, (B) hydrophobic, (C)negatively charged, (D) polar, (E) positively charged, (F) six-membered rings, and (G) five-membered rings.
