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:

  • click the Settings button in the FEP+ Panel.

  • choose Advanced Options from the Settings button menu in the FEP+ Panel

  • 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.

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). Opens a file selector in which you can browse to and select the Force Field Builder project (*_ffb.zip) where the custom force field parameters are stored.

This button is only available when you select Use customized version.

Custom charges option menu

Choose a method for handling custom ligand charges. The custom charges are generated by running Jaguar calculations on the ligands, using generate_custom_charges, and are stored in the Maestro file with the ligand structures.

  • Assign—Assign a new set of custom ligand charges to the ligand atoms, by running Jaguar calculations for fitting of the charge parameters.
  • Keep—Use the custom ligand charges that were generated previously.
  • Clear—Delete the custom charges and use the default charges (cm1a/bcc charges).
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. 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.

Run membrane protocol option

Run the default membrane equilibration protocol.

If the system does not have a membrane, the POPC membrane 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.

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+.

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.

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