FEP Solubility Panel

Calculate the aqueous solubility of a set of ligand-sized molecules, from FEP calculations that model the dissolution of a solid form of the molecule in water. Results are available in a CSV file.

To open this panel: click the Tasks button and browse to Free Energy Perturbation → Solubility FEP.

This panel is docked into the Workspace by default, so you can easily switch focus from the panel to the Workspace. You can undock the panel if you want to place it somewhere else. To dock or undock the panel, use the docking button in the title bar (left of the Close button) .

  • Overview
  • Using
  • Features
  • Additional Resources

Overview of FEP Solubility

The free energy of solubility of a ligand-sized molecule is determined by considering the transfer of a molecule from the surface of a solid in contact with the solvent into bulk solvent. For the purposes of the simulation, the process can be broken into two parts: (1) sublimation, where a molecule is removed from the solid into the gas phase, and (2) solvation, where the molecule is transferred from the gas phase to the solution phase—or, in the actual simulation, from the solution phase to the gas phase. The difference of the free energy for these two processes is the free energy of solubility.

Ln(s) → Ln-1(s) + L(g)

ΔG(sublimation)

L(solv) → L(g)

−ΔG(solvation)

Ln(s) → Ln-1(s) + L(solv)

ΔG(solubility) = ΔG(sublimation) + ΔG(solvation)

Two alchemical FEP simulations are performed, both of which involve annihilation of a ligand molecule. In the first, a molecule on the surface of the solid phase that is in contact with the solvent is annihilated (sublimation). In the second, a molecule in pure solvent is annihilated (desolvation). For both simulations, existing solvent molecules fill the space that was occupied by the ligand. The simulations are done in the NPT ensemble so that the densities of solvent and solid are maintained.

The solid phase can be represented by an amorphous cluster of 64 molecules or a crystal structure. The cluster is built from a single ligand structure by arranging the molecules in a simulation box, minimizing the overall volume while avoiding steric clashes. MD relaxation simulations of this cluster of molecules is then performed, followed by a production equilibration MD simulation at 300 K in the NPT ensemble. The structure from the final frame of this simulation is then merged into a pre-equilibrated water box, removing water molecules that overlap with the ligand molecules.

Alternatively, you can use a crystal structure that has at least eight copies of the ligand. Like the amorphous cluster, the structure is merged into a pre-equilibrated water box, removing overlapping water molecules.

The system is immersed in the solvent on all sides, with a 10 Å buffer. (This is the distance from the cluster to the box boundary, and hence the depth of the solvent. Thus the minimum distance between two clusters, which are in different cells, is 20 Å.) The system is therefore simulating a very small particle that is dissolving in the solvent.

The sublimation simulations are repeated 5 times and the solvation simulations are run once, for the molecules with the highest solvent exposure. The solubility free energy is taken as the median value from the results of these simulations.

Using the FEP Solubility Panel

FEP calculations can use a large amount of memory. There is a script that you can use to estimate the memory required for an FEP job—see fep_memory_estimation.py Command Help for more information. You can estimate the number of atoms by building the initial system, including solvent, in the System Builder Panel. With a solvent buffer of 8 Å, the output structure approximately provides an upper limit to the size of the FEP systems. This information is needed to estimate the memory required.

You can choose to only run the solvation FEP simulations by selecting the Use Hydration mode only option from the Advanced Options.

As starting structure, use a single ligand, or a crystal structure with at least 8 copies of the ligand..

FEP Solubility Panel Features

Use ligands from option menu

Choose the structure source for the solubility simulations. You can use either a single ligand per entry or a crystal structure with at least 8 copies of the ligand. The structures must meet Maestro critieria for ligands, and must not be charged .

  • Project Table (n selected entries)—Use the entries that are currently selected in the Project Table or Entry List. The number of entries selected is shown on the menu item. An icon is displayed to the right which you can click to open the Project Table and select entries.
  • Workspace (n included entries)—Use the entries that are currently included in the Workspace, treated as separate structures. The number of entries in the Workspace is shown on the menu item. An icon is displayed to the right which you can click to open the Project Table and include or exclude entries.
  • File—Use the specified file. When this option is selected, the File name text box and Browse button are displayed.
Open Project Table button

Open the Project Table panel, so you can select or include the entries for the structure source.

File name text box and Browse button

Enter the file name in this text box, or click Browse and navigate to the file. The name of the file you selected is displayed in the text box.

Load button

Load the ligands from the ligand source into the ligands table. A check is run to ensure that the structures meet Maestro's criteria for a ligand. Any structure that does not meet these criteria is not loaded, and a warning is issued indicating how many ligands were not loaded. The ligands are added to the Project Table as locked entries.

Number of ligands text

This text reports the number of ligands loaded and listed in the table. If there are ligands for which force field parameters are not available, a button with a warning icon is displayed next to the text. Click this button to open the Force Field Builder - OPLS4/OPLS5 Panel, to generate the missing parameters. If any ligands fail the health test, an icon is displayed next to the text, with a tooltip that indicates how many of the ligands failed and consequently will be excluded from the calculations (skipped).

Ligands table

Lists the imported ligands. The Title column displays the 2D structure in a tooltip when you pause the pointer over a title. The Quality column shows an icon indicating the status of the ligand health report. The tooltip gives a description of the issues found with the ligand. Ligands that fail any of the criteria for a valid ligand show a red error icon, and are excluded from the calculation. A tooltip gives the reason for excluding the ligand.

You can select multiple ligands in the table for deletion. You can click the column heading to sort by that column.

Delete button

Delete the selected ligands from the table.

Advanced Options button

Set total times for various simulations in the workflow. Opens the FEP Solubility - Advanced Options Dialog Box.

Job toolbar

Manage job submission and settings. See Job Toolbar for a description of this toolbar.

The FEP+ tasks are run on the GPU host chosen in the the Job Settings Dialog Box. Typically, three subjobs are submitted per perturbation (for complex, solvent, vacuum). You can set Maximum simultaneous FEP subjobs to limit the number of subjobs on the GPU host at the same time.

The Job Settings button menu contains a Reset item, to reset the panel settings, and a Write item, for writing job files, including scripts for extending and restarting the simulation.

If you have purchased Web Services, the Submit to Web Services option is present. Select to upload the job to Web Services for execution, and click the Submit button. The number of credits to be used and the number of available credits are reported, and the job is uploaded on confirmation of the credit usage for the job. If you have access to multiple Web Services projects, you are prompted to choose the project to associate the job with. The FEP+ Web Services Job Table Panel opens.

If you have Web Services credentials but do not see the Submit to Web Services option, see Troubleshooting.

The Job Settings button opens the FEP Solubility - Job Settings Dialog Box, where you can make settings for running the job.

Status bar

The status bar displays information about the current job settings and status for the panel. The settings includes the job name, task name and task settings (if any), number of subjobs (if any) and the host name and job incorporation setting. The job status can include messages about job start, job completion and incorporation.

Use the Reset button to reset the panel to its default settings and clear any data from the panel. You can also reset the panel from the Job toolbar.

The status bar also contains the Help button , which opens the help topic for the panel in your browser. If the panel is used by one or more tutorials, hovering over the Help button displays a button, which you can click to display a list of tutorials (or you can right-click the Help button instead). Choosing a tutorial opens the tutorial topic.

Tutorials

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