FEP+ Settings Dialog Box

Set simulation options for relative and absolute binding FEP+ calculations and set settings for the behavior of FEP+ Panel actions.

To open this dialog box:

  • Features
  • Additional Resources

FEP+ Settings Dialog Box Features

The sections that are available depend on whether the simulation is for relative or absolute binding affinity, solubility, or protein mutation.

Force Field section

Select an option for the source of custom OPLS parameters, and for generating missing parameters. Once selected, the source is used within the current instance of the FEP+ panel until the panel is closed or the source is changed again. The options available depend on your license.

Force field option menu

Choose the force field for the simulations. The choices are OPLS4 or OPLS5. The default is OPLS4, unless you set the default in the Force Field settings section of the Preferences Panel.

OPLS5 Metals force field options button ()

Click this button to open a popdown pane with options for enabling the OPLS5 Metals force field. This button is only displayed when OPLS5 is selected as the force field.

Enable OPLS5 Metals force field (beta) option

Select this option to use the OPLS5 Metals force field for systems containing supported metals. The supported metals are Ca, Fe, Ir, Mg, Pt, Zn. The OPLS5 Metals force field is significantly slower than the standard OPLS5 force field. Only available after the input structures have been analyzed successfully and the criteria for using the OPLS5 Metals force field has been met.

Analyze Structures button

Click this button to analyze the input structures and determine whether the OPLS5 Metals force field can be used. The analysis checks that the structures contain supported metal elements and that the coordination environment around each metal center is compatible with the OPLS5 Metals force field. If the structures meet the criteria, the Enable OPLS5 Metals force field (beta) option becomes available. If the input structures change after the analysis, the analysis must be repeated.

Use customized version option

Use your customized version of the OPLS force field, rather than the standard version in the distribution. This option is set by default to the value of the Use custom parameters by default option in the Preferences panel, under Jobs - Force field, when the current panel is opened. The default directory for the customized version can also be specified as a preference, in the same location.

If the customized version is missing or invalid, the text of this option turns orange and an orange warning icon is displayed to the right, with a tooltip about the problem.

Parameter set button

Select the set of custom parameters for the OPLS force field. Opens the Set Custom Parameters Location Dialog Box.

Generate missing parameters with Force Field Builder option

Run the Force Field Builder to generate any missing force-field torsional parameters before running the FEP+ job.

Merge Parameters button

Merge a set of custom force field parameters into the current custom parameters file (defined in the Set Custom Parameters Location Dialog Box, see Force Field settings for information).

The panel automatically detects the Force Field Builder project (*_ffb.zip) where the custom force field parameters are stored, based on the input file name and path. A confirmation dialog is displayed before merging.

This button is only available when a Force Field Builder project is present in the current working directory.

Custom charges option menu

Choose a method for handling custom ligand charges. Custom charges are molecule-specific partial charges generated from Jaguar ESP calculations. FEP+ assigns custom charges by default.

  • Assign—Assign a new set of custom ligand charges to the ligand atoms by running Jaguar calculations. This is the default.
  • Keep—Use custom ligand charges that are already stored with the ligand structures. Select this option if you have previously generated charges, for example by running generate_custom_charges to use charges based on a different ligand conformer.
  • Clear—Delete any existing custom charges and use the older cm1a/bcc-based charges instead.
Simulation Parameters section

Set parameters for the MD simulations.

Ensemble option menu

Choose the ensemble in which to run the simulation. The choices are NPT, NVT, and μVT. The default is μVT.

The μVT ensemble is used for GCMC sampling of water molecules. It has a variable number of water molecules with a fixed chemical potential (μ) and a fixed number of solute atoms (N). See Grand Canonical Monte Carlo Addition of Water for more information.

Equilibration time (ns) text box

Set the simulation time for unrestrained equilibration before the FEP simulations, in nanoseconds. The default is 0.02 ns.

Simulation time (ns) text boxes

Shows the simulation times for the Complex/Solvent/Vacuum (or Complex/Solvent/MD for absolute binding affinity or Complex/Solvent/Fragment for protein FEP or Hydration/Sublimation for solubility FEP) legs of the simulation. Select match to set the same simulation time for all legs. Set the simulation time to 0 to skip that leg for relative FEP calculations. For absolute binding affinity calculations, the minimum simulation time is 0.5 ns. The stages include:

  • Complex—Set the simulation time for the complex leg of the FEP simulations, in nanoseconds. The default is 5 ns.
  • Solvent—Set the simulation time for the solvent leg of the FEP simulations, in nanoseconds. The default is 5 ns.
  • Vacuum—Set the simulation time for the vacuum leg of the FEP simulations, in nanoseconds. The default is 5 ns. Only available for relative binding affinity.
  • MD—Set the simulation time for the production molecular dynamics simulation, in nanoseconds. The default is 1 ns. Only available for absolute binding affinity.
  • Fragment—Set the simulation time for the fragment leg of the FEP simulations, in nanoseconds. The default is 5 ns. Only available for protein FEP.
  • Hydration—Set the simulation time for the hydration (or solvation) leg, in which a single solvated ligand molecule is removed from the solvent. The default is 5 ns. Only available for solubility FEP.
  • Sublimation—Set the simulation time for the hydration (or solvation) leg, in which a ligand molecule is removed from the aggregate. The default is 5 ns. Only available for solubility FEP.
Random seed text box

Set the seed for random number generation. This is used, for example, to randomize velocities. Setting the seed ensures that the same random numbers are generated for each simulation, which allows you to reproduce the simulation.

Sampling section

Set options for the sampling.

Number of λ-windows option menus

Specify the number of lambda windows for different perturbation types. The default values are different for standard side-chain perturbations, perturbations of the core part of the ligand, and perturbations that change the ligand charge. Only present for relative binding FEP.

Default option menu

Choose the number of lambda windows for default perturbation types, from the values on the menu.

Core-hopping option menu

Choose the number of lambda windows for perturbations of the ligand core, from the values on the menu.

Charge-hopping option menu

Choose the number of lambda windows for perturbations that change the charge on the ligand, from the values on the menu.

Enhance sampling of dihedrals option

Enhance the sampling of dihedrals by lowering the rotation barrier. Only available for Relative FEP jobs.

System Builder section

Set parameters for the construction of the Desmond model system used for the simulations.

Water model option menu

Specify the water model to implement. The available water model options are SPC, SPCE, TIP3P, TIP3P_CHARMM, TIP4P, TIP4PEW, TIP4P2005, TIP5P, and TIP4PD. This option menu is not available for the FEP Solubility Panel or the Absolute Binding FEP+  Panel.

Buffer size text box

Specify the buffer distance between the solute structures and the simulation box boundary. The default is 5 Å in the complex leg, but 8 Å in the complex leg for charge perturbations; 5 Å in the solvent leg of protein-residue mutation FEP; 10 Å in solubility FEP; 10 Å in the solvent leg of other types of FEP. This feature is disabled for systems that contain membranes.

The value you set here is used only if it's greater than the corresponding default value; in other words, you can only increase the buffer size. A buffer size that is too small may result in self-interactions (that is, interaction of the complex with an image of itself in a neighboring cell).

Proteins that are elongated can rotate during the simulation, bringing the protein closer to its image in the neighboring cell, or even clashing with its image. Increasing the buffer size can be used to alleviate this problem and allow for rotation. The size of the increase depends on factors like the length and width of the protein and its orientation in the box. Aligning the protein's largest distance along a coordinate axis beforehand reduces the likelihood of clashes on rotation, and the increase in the buffer size can be smaller. If, in addition to alignment, you also edit the input file and make sure that the box is cubic, there may be no need to increase the buffer size to allow for rotation. See Preparing Protein and Ligand Structures for FEP+ for information on alignment of the protein.

Use Scan mode option

Select this option to run a faster absolute binding FEP+ protocol that has a lower computational cost and lower accuracy. This protocol truncates the receptor and halves the number of lambda windows. An information button next to the option shows a summary.

Only present for absolute binding FEP+ calculations. Not available when the input contains a membrane.

Scan mode cannot be combined with the membrane protocol or with receptor restraints. When you select this option, the Run membrane protocol option and the Receptor restraint settings are cleared and disabled. If either is set, a dialog box first asks you to confirm the change. When you load a map that was run in scan mode, this option is selected and cannot be changed.

Run membrane protocol option

Run the default membrane equilibration protocol.

If the system does not have a membrane, a membrane of the selected type is added, and placed automatically. The system is oriented in the membrane according to the OPM convention: the membrane is placed perpendicular to the z axis with the coordinate origin at the center of the membrane. If you need to reorient your receptor structure, you can use the adjustment tools (see Adjusting Structures). A good option is to align the receptor to a similar structure from the OPM database.

Selecting this option disables the Water model and Buffer size options.

Membrane type option menu

Choose the type of lipid bilayer to build for the membrane. The default is POPC @ 300K. Only available when Run membrane protocol is selected.

Add salt option and text box

Add salt (NaCl) to the system at the concentration specified in the text box, in mol dm-3. The default represents the approximate physiological salt concentration.

Receptor restraint section

In this section you can set restraints on selected atoms in the receptor, with a specified force constant. This section contains a standard set of picking tools that you can use to select atoms.

Only present for relative FEP+ and absolute binding FEP+.

Force constant text box

Specify the force constant to be applied to the atoms selected for restraint.

Project Interactions section
When nodes in the map are selected section

Specify the action taken for display or selections of the structures in the project when nodes are selected in the map.

Include entries in Workspace option

Include the entries for the nodes in the Workspace.

Include receptor in Workspace option

Include the receptor in the Workspace.

Select entries in Project option

Select the entries for the nodes in the FEP+ entry group in the Project Table and Entry List.

When the panel is closed section

Specify what happens to the FEP+ entries when the panel is closed.

  • Keep entries in Project—leave the entries in the project, in their entry group. The entry group becomes a normal entry group, with no link to the FEP+ Panel.

  • Remove entries from Project—remove the FEP+ entry group from the project. This deletes all information from the project for these entries. If you choose this option, you should export any information you want to keep from the FEP+ panel, e.g. as an .fmp file.

Reset button

Reset the dialog box to its default settings, clearing all data.

Edit Model button

Access all parameters for the FEP calculation. Click on the pencil icon to make changes.

Manage Settings button menu

Import or export the current simulation settings as a protocol (.yaml) file. Not available for absolute binding FEP calculations.

Export to file button

Export the current simulation settings to a protocol (.yaml) file. Opens a file selector in which you can specify the file name and location.

Import from file button

Import simulation settings from a protocol (.yaml) file. The file is validated for FEP type compatibility, ensemble values, lambda window ranges, and positional restraint constraints before the settings are applied. Opens a file selector in which you can choose the file.

Related Topics