Graphical User Interface Quickstart¶

This chapter provides a step-by-step introduction on how to use the SilcsBio Graphical User Interface (GUI).

Remote server setup¶

The SilcsBio GUI is designed to work with the server installation of the SilcsBio software. Therefore, the remote server needs to be configured to properly use the GUI. When you launch the GUI, you will be presented with the Home page. From the Home page, select Settings and remote server configuration.

Within the “Settings” page, select Server and enter the remote server information, such as Server Address, Username, and an SSH key to the server. If you do not have an SSH key to the server, leave it blank. The GUI will ask you the password to the remote server instead. Select the “Make default server” checkbox if you would like to set this server as your default server. This server will be selected as a default in other parts of the GUI.

You will also need to enter SILCSBIODIR and GMXDIR file path values. These should match the values on your remote server. Please contact support@silcsbio.com for assistance.

Once all information is entered, click the “Save” button. The GUI will save the information and confirm that you have a working connection to the server.

SILCS simulation¶

To begin a new SILCS project, follow these steps:

Select New SILCS project from the Home page.
Enter a project name, select your remote server, and select a project location file folder on the remote server. Typical SILCS simulations produce output files in excess of 100 GB, so please select a project location file folder with appropriate storage capacity.

Next, select a protein PDB file. We recommend cleaning your PDB file before use, incuding keeping only those protein chains that are necessary for the simulation, removing all unnecessary ligands, renaming non-standard residues, filling in missing atomic positions, and, if desired, modeling in missing loops.

If the GUI detects missing non-hydrogen atoms, non-standard residue names, or non-contiguous residue numbering, it will inform the user and provide a button labeled “Fix?”. If this button is clicked, a new PDB file with these problems fixed and with _fixed added to the base name will be created and used in the SILCS simulation.
Once all information is entered correctly, press the “Setup” button at the bottom of the page. The GUI will contact the remote server and perform the SILCS GCMC/MD setup process.

During setup, the program automatically performs several steps: building the topology of the simulation system, creating metal-protein bonds if metal ions are found, rotating side chain orientations to enhance sampling, and putting probe molecules around the protein. To complete the entire process may take up to 10 minutes depending on the system size. A green “Setup Successful” button will appear once the process has successfully completed. Press this button to go to the next step.
Your SILCS GCMC/MD simulation can now be started by clicking the “Run SILCS Simulation” button. Before running, you may wish to double check that you have chosen the desired file folder on the remote server and that it has 100+ GB of storage space.

10 compute jobs will be submitted to the queueing system on your remote server. Job progress will be displayed in this same window. The status of each job is shown next to its progress bar: “Q” for queued, “R” for running, and “E” for finished. At this point, your jobs are in progress and you may safely quit the SilcsBio GUI or go back to the Home page to do other tasks.

If a job encounters an error and did not finish, the status of the job will show “F” for failed. A “restart” button will appear next to the status. If the restart button is used, the job will be resubmitted to the queue and continue from the last cycle of the calculation.
To see a full listing of all of your projects, select Continue SILCS project from the Home page. This will show the complete list of all SILCS projects you have set up on the local machine where you are currently running the SilcsBio GUI, as well as the status of each project.

To resume work on a project or check the status of associated compute jobs you previously started, simply click the project name in the list.
Once your SILCS project compute jobs are finished, the GUI can be used to create FragMaps and visualize them. Confirm project location and the input protein PDB file are correct. Select the reference PDB file to be used to generate FragMaps. Generally, this reference PDB file is the same as the protein PDB file. A different file with the protein in a different orientation can be selected if you want to generate FragMaps relative to that orientation. Click “Generate FragMap” to generate FragMaps and download them to the local computer for visualization.

Tip

If you plan to compare FragMaps from two different protein structures, you will want to generate them with the same orientation. In that case, pre-align your input structures with each other and use these aligned coordinates as your Reference PDB Files.

For additional details, please see SILCS: Site Identification by Ligand Competitive Saturation.

SILCS-MC simulation¶

Select New SILCS-MC project from the Home page.
Enter a project name and select your remote server. On the remote server, select the “FragMap Location,” which is the directory that contains your FragMaps, and the “Protein PDB File,” which is the file that was used for the SILCS simulations. Also select the “Reference Ligand File,” which must be an SD or Mol2 format file on the local filesystem that contains the parent ligand aligned in the binding pocket of the Protein PDB File.
Once all information is entered correctly, press the “Setup” button at the bottom of the page. The GUI will contact the remote server and upload the SD or Mol2 file to the “Project Location” directory on the remote server. A green “Setup Successful” button will appear once the upload has successfully completed. Press this button to proceed.
The GUI will display a summary screen with the Project Name, Remote Server, Project Location, Protein PDB File, Ligand SDF/Mol2 File, and Ligand Modifications. The entry for Ligand Modifications will state “0 modifications saved” and have a button labeled “Add Ligand Modifications.” Press this button to select modifications to the parent ligand for evaluation by SILCS-MC.
This will show the parent ligand in the binding pocket, and the binding pocket atoms may be visualized in licorice or surface representation. There are two major modification types, Substitution and Replacement, available in the GUI. Substitution is used to substitute an atom with a functional group. Replacement is used to replace an atom in a ring with another functional group that preserves the ring.

In the visualization window, select the atom to be modified. Then, select your desired modifications from the “Substitution” or the “Replacement” tab in the right-hand panel. Pressing the “Save” button in the panel will take you to the “Review” tab.

The list of modification types in the GUI covers a very broad range of chemical functionality and size.
Use the “Review” tab to confirm your desired modifications.

Valid modifications will have a small Image icon as well as a small Trash Can icon. Clicking on the Image icon will show the modification in the center panel. Clicking on it again will show the parent ligand. Clicking on the Trash Can icon will delete the proposed modification from your list. You can go back to the “Substitution” and “Replacement” tabs to add to your list. Once you have completed your list of modifications, you must press the “Save Modification” button in the “Review” tab to actually save the list of modifications for your project.
Once you have saved all your desired modifications, click on SILCS-MC in the left-hand panel to go back to the summary screen. The “Ligand Modifications” will have been updated to reflect the number of saved modifications that will be evaluated by SILCS-MC.

Clicking the “Run SILCS-MC” button will cause the GUI to contact the remote server, upload the modifications to the parent ligand, and submit the SILCS-MC jobs.

You can monitor job progress in the SilcsBio GUI, and click on the “Show Chart” button once all jobs are at 100%.
Clicking the “Show Chart” button after jobs have reached 100% will download the SILCS-MC results from the server. Click on “Data collection finished” to proceed.

The “Chart” tab in the right-hand area will list the number of favorable and unfavorable modifications associated with a particular modification site. Click on the modification site to see the change in Ligand Grid Free Energy (\(\Delta LGFE\)) relative to the parent ligand for each modification at that site.

For additional details, please see SILCS-MC: Posing and Scoring Ligands Using FragMaps.

SSFEP simulation¶

Select New SSFEP project from the Home page.
Enter a project name, select your remote server, and select a project location file folder on the remote server. Typical SSFEP simulations produce output files in excess of 20 GB, so please select a project location file folder with appropriate storage capacity.

Next, select a protein PDB file and a ligand file. The ligand should be aligned to the binding pocket in the accompanying protein PDB file. We recommend cleaning your PDB file before use, incuding keeping only those protein chains that are necessary for the simulation, removing all unnecessary ligands, renaming non-standard residues, filling in missing atomic positions, and, if desired, modeling in missing loops.

If the GUI detects missing non-hydrogen atoms, non-standard residue names, or non-contiguous residue numbering, it will inform the user and provide a button labeled “Fix?”. If this button is clicked, a new PDB file with these problems fixed and with _fixed added to the base name will be created and used in the SSFEP simulation.
Once all information is entered correctly, press the “Setup” button at the bottom of the page. The GUI will contact the remote server and perform the SSFEP setup process.

During setup, the program automatically performs several steps: building the topology of the simulation system, creating metal-protein bonds if metal ions are found, rotating side chain orientations to enhance sampling, and putting probe molecules around the protein. To complete the entire process may take up to 10 minutes depending on the system size. A green “Setup Successful” button will appear once the process has successfully completed. Press this button to proceed.
Your SSFEP simulation can now be started by clicking the “Run MD Simulation” button. Before running, you may wish to double check that you have chosen the desired file folder on the remote server and that it has 20+ GB of storage space. There are two parts to SSFEP: a compute-intensive MD simulation and a very rapid \(\Delta \Delta G\) calculation. The compute-intensive MD may take several hours, and is done only once. The rapid \(\Delta \Delta G\) calculation part relies on the MD results and is able to test thousands of functional group modifications to your parent ligand in under an hour. Should you wish to test additional modifications to your parent ligand at a later time in the project, there is no need to re-run the compute-intensive MD, which makes SSFEP a very efficient method.

10 compute jobs will be submitted to the queueing system (five for the ligand and five for the protein:ligand complex) on your remote server. Job progress will be displayed in this same window. The status of each job is shown next to its progress bar: “Q” for queued, “R” for running, and “E” for finished. At this point, your jobs are in progress and you may safely quit the SilcsBio GUI or go back to the Home page to do other tasks.

If a job encounters an error and did not finish, the status of the job will show “F” for failed. A “restart” button will appear next to the status. If the restart button is used, the job will be resubmitted to the queue and continue from the last cycle of the calculation.
While your jobs are running, you can prepare your ligand modifications with the “Add Ligand Modifications” button.

This will show the parent ligand in the binding pocket, and the binding pocket atoms may be visualized in licorice or surface representation. There are two major modification types, Substitution and Replacement, available in the GUI. Substitution is used to substitute a hydrogen with another functional group. Replacement is used to replace an atom in a ring with another functional group that preserves the ring.

In the visualization window, select the atom to be modified. Then, select your desired modifications from the “Substitution” or the “Replacement” tab in the right-hand panel. Pressing the “Add” button in the panel will update your list of modifications. The list of modification types in the GUI covers a broad range of chemical functionality. Custom modifications can be made using the Command Line Interface (CLI) as detailed in SSFEP: Single Step Free Energy Perturbation.
Use the “Review” tab to confirm your desired modifications.

Valid modifications will have a small Image icon as well as a small Trash Can icon. Clicking on the Image icon will show the modification in the center panel. Clicking on it again will show the parent ligand. Clicking on the Trash Can icon will delete the proposed modification from your list. You can go back to the “Substitution” and “Replacement” tabs to add to your list. Once you have completed your list of modifications, you must press the “Save modification” button in the “Review” tab to actually save the list of modifications for your project.

Once the MD simulation stage has finished, the GUI will analyze your list of modifications and create a chart. SSFEP is designed to evaluate small modifications and results are best interpreted qualitatively. Therefore GUI-created charts indicate the predicted change in direction of the binding affinity relative to the parent ligand.

For additional details, please see SSFEP: Single Step Free Energy Perturbation.