FEP+ Advanced Options Dialog Box

Set simulation options for FEP calculations for ligand binding, ligand selectivity, protein mutation.

To open this dialog box, choose Advanced Options from the Settings button menu in the relevant panel.

  • Features
  • Additional Resources

Advanced Options Dialog Box Features

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

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

Shows the simulation times for the Complex/Solvent/Vacuum (or Complex/Solvent/MD for absolute binding affinity or Complex/Solvent/Fragment for protein FEP) legs of the simulation. Click the Edit link to change the simulation time for various legs of the FEP simulations, in nanoseconds. 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.
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.

Ligand charges section

This section is not available for protein mutation FEP jobs.

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).
Solvation Free Energy section

Make settings for calculation of the solvation free energy of the ligands. This can only be done for small-molecule ligands that are not covalently bound, and for perturbations that do not involve charged ligands. Only present for relative binding FEP.

Calculate relative solvation option

Select this option to perform ligand FEP calculations in vacuum, to obtain relative solvation free energies. The results are stored in the .fmp file and are reported in the FEP+ Panel — Analysis Tab. This option is selected by default.

This option is not available for protein mutation FEP jobs.

Ligand Restraints section

Set restraints on the ligand during the simulation, in addition to any protein-ligand restraints.

This section is only present for absolute binding FEP.

Apply dihedral restraints on the ligand molecule option

Apply restraints to dihedrals in the ligand molecule, for rotatable bonds and 6-membered aliphatic ring motions. This may be necessary if the protein-ligand restraints are insufficient to ensure that the ligand maintains its pose relative to the protein. These restraints are also determined from the MD simulation. The force constant for the restraints is 40 kcal mol−1 rad−2. Note that applying restraints can improve convergence, but the conformational sampling is limited by the restraints.

This option may be useful if you want to rank order ligand binding poses that do not differ too much and might interconvert in MD simulations. By turning on this option, rotatable bonds in the ligand are harmonically restrained to the initial value in the intermediate lambda windows, so that ligands will likely stay close to the initial pose, allowing the relative stability of the two poses to be ranked.

OPLS Settings 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.

Reset button

Reset the settings in the dialog box to their default values.

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