FEP+ Pose Builder Panel

Generate FEP+ ready poses using a workflow integrating reference ligand selection, ligand alignment, and clash resolution.

To open this panel: Clickclick the Tasks button and browse to Structure Alignment → FEP+ Pose BuilderClickclick the Tasks button and browse to FEP+ → FEP+ Pose Builder.

  • Using
  • Features
  • Additional Resources

Using the FEP+ Pose Builder Panel

The FEP+ Pose Builder Panel is a workflow integrating reference ligand selection, ligand alignment, and clash resolution aiming for generating FEP+ ready poses, and is Schrödinger’s preferred tool for pose generation for FEP+. It has outperformed other methods on benchmarks, and incorporates many of the best practices shown in Pose Generation for FEP that would otherwise have to be done manually.

Job Server is required for submission of FEP+ Pose Builder jobs. To learn more about Job Server, see Job Submission to a Cluster.

The features of the FEP+ Pose Builder Panel are contained almost entirely in five sections, which are described in depth in the Features section. With the exception of the Specify Ligands and Align Ligands sections, the other sections can be enabled or disabled using the checkmark icon located to the left of the section name. Disabled sections appear in gray and are not utilized in the task to be performed.

To begin, upload a ligand file in the Specify Ligands section. The label at the top left of the area reflects the uploaded file. In the Prepare Ligands section, you can click on the More Options link to open up a pane with additional options. In the Filter Prepared Ligands section, you can either load a file in using the Browse button, or create a file by pressing on the Create button which links to the Ligand Filtering Panel. In the Align Ligands section, you can upload a file of reference ligands. Use the Reference selection option menus to select various options. In the Resolve Clashes section, you can simply upload a receptor file.

You can provide membrane structure components (e.g. POPC and water box) together with receptor structures. In order to associate membrane structures with the receptor structure, especially when multiple receptors are used, you must group the receptor structure with the membrane structures together in Maestro. The membrane structures are not used in clash resolution if the ligand binds at the interface.

The alignment program used (-align_program) depends on the ligand type and alignment mode. For small molecule ligands with core alignment, align_ligands is used when one pose is generated per ligand, and confgen is used when multiple ring-snapping poses are generated. For macrocyclic ligands (10 or more ring atoms) and small molecule ligands with R-group alignment (core hopping alignment), tug_align is used. Because tug_align incorporates ligand alignment and clash resolution by rejecting clashing conformations during alignment, the separate clash resolution stage is skipped and the related options are ignored. The alignment program can only be set from the command line.

You can set how ligands are aligned to a common core with the Define common core with option menu in the Align Ligands section settings.

FEP+ Pose Builder can also generate poses for covalent ligands (-ref_to_cov_settings_map). The covalent reaction for each reference is defined by a reaction type from CovDock (Covalent Docking) or a custom reaction file. The reference ligand is supplied in its unreacted form, with the reactive group present and no covalent bond to the receptor, and the aligned ligands are returned as covalent protein-ligand complexes. Covalent pose generation can only be set from the command line.

The panel outputs the following set of metrics for assessing the pose quality:

 

Pose Metrics Description
pose similarity (Core group)%+ Shape Similarity * (Non-core groups)%
fep similarity Similarity score of the FEP edge between reference and aligned ligands
core rmsd RMSD of core atoms between reference and aligned ligands
rgroup shape sim Shape similarity of non-core region
shape sim Shape similarity of whole ligands
num ring spears Number of ring spears between aligned ligand and receptor
num steric clashes Number of steric clashes between aligned ligand and receptor

 

To write out the input file and a script for running the job from the command line, click the arrow next to the Settings button and choose Write. For information on command usage and options, see fep_pose_builder.py Command Help.

FEP+ Pose Builder Panel Features

Note: With the exception of the Specify Ligands and Align Ligands sections, the other sections can be enabled or disabled using the checkmark icon located at the left of the section name. Disabled sections appear in gray and will not be utilized in the task.

Specify Ligands

Select ligands to process. The number of ligands loaded into the panel is displayed as text to the right of the section name.

Ligands to process option menu

Choose the structure source for the ligands. You can load 2D or 3D structures.

  • Project Table (n selected)—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. Click the Load button to load the entries into the panel.
  • Workspace (n 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. Click the Load button to load the entries into the panel.
  • File—Use the specified file. Click the Browse button to navigate to the file.
Prepare Ligands section

Adjust various parameters for ligand preparation.

pH text boxes

Enter a numerical value for the pH in the pH text box, with the range in pH value specified in the +/- text box. The values can be specified to two decimal places, and the values can be adjusted using the arrow buttons.

Generate tautomers option

Select this option to generate tautomers. This option is disabled by default.

More Options link

Click to open a separate pane with the following options:

  • Add Epik metal binding states option—Select this option to add Epik metal binding states during ligand preparation.

  • Obtain stereochemical information from options—Select either Specified 2D stereo properties or 3D geometry for obtaining the stereochemical information.

  • Unspecified stereocenters—use the text box to define the number of stereoisomers to retain.

Filter Prepared Ligands section

Define the criteria for ligand filtering. You can define it manually or load a file. Matching ligands are kept.

Define link

Click to open the Ligand Filtering Panel, where you can set up filtering criteria for a set of structures.

Load File link

Click to select a Ligrep Filter file (*.lff) for defining filtering criteria.

Align Ligands section

Specify aligned 3D structures.

Reference Ligands option menu

Choose the structure source for the ligands.

  • Project Table (n selected)—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. Click the Load button to load the entries into the panel.
  • Workspace (n 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. Click the Load button to load the entries into the panel.
  • File—Use the specified file. Click the Browse button to navigate to the file.
Settings icon

Click to open a dialog box with settings for ligand alignment.

Max poses per ligand text box

Specify the maximum number of poses to return for each ligand. Multiple poses are returned only for ligands that have asymmetric rings in their R-groups, where different ring flips can occur during alignment.

Define common core with option menu

Choose how the common core used for ligand alignment is determined. The default is MCS or BM (best alignment).

  • Maximum Common Substructure (MCS)—Use the maximum common substructure, in which all atoms are distinguished and only complete rings are included.
  • Bemis-Murcko scaffold (BM)—Use the Bemis-Murcko scaffold, which includes all ring systems and connecting linker atoms, with terminal side chains removed. All heavy atoms are treated as equivalent, but bond types are distinguished.
  • MCS or BM (best alignment)—Generate both the MCS and the Bemis-Murcko core, and keep the one that gives the better alignment.
  • MCS or BM (largest core)—Generate both the MCS and the Bemis-Murcko core, and use the larger of the two.
  • SMARTS—Use the SMARTS pattern defined for reference selection as the core. Supported only when a core SMARTS pattern is used for reference selection. If a ligand does not match a SMARTS pattern, MCS or BM (largest core) is used for that ligand.

The common core definition does not apply to macrocycles, or to ligands that are aligned on R-Group SMARTS.

Reference selection option menus

  • Fixed Reference—Use a fixed reference to align ligands. Choose a reference from the second option menu. If this option is selected, the Align R-Groups option is present and can be used to define rules for alignment. Ligands that do not match the defined rules are aligned using common cores.

  • SMARTS or Similarity—Use the Define SMARTS link to define SMARTS patterns for selecting a reference. You can define SMARTS for R-groups or the common core between the ligand and reference. If the defined SMARTS pattern is for R-groups, it is used for alignment in addition to reference selection.

    If a match is not found using the defined SMARTS patterns, similarity matching is used for reference selection and ligand alignment. Choose whether to use 2D Similarity or FEP+ 3D Similarity from the second option menu.

  • Similarity Only—Use similarity matching for reference selection and ligand alignment. Choose whether to use 2D Similarity or FEP+ 3D Similarity from the second option menu.

Align R-Groups option

Select this option to define rules for aligning R-groups using the Define SMARTS link. Only present if Fixed Reference is selected.

Define SMARTS link

Click the link to open the Define SMARTS Dialog Box. The number of definitions is displayed as text to the right of the link. Only present if Fixed Reference or SMARTS or Similarity is selected.

Resolve Clashes section

Identify the prepared structure.

Receptor option menu

Choose the structure source for the receptor. Multiple receptors can be selected.

  • Project Table (n selected)—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. Click the Load button to load the entries into the panel.
  • Workspace (n 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. Click the Load button to load the entries into the panel.
  • File—Use the specified file. Click the Browse button to navigate to the file.
Map to References link

When there are multiple receptors selected, click to define the receptor mapping for each reference. A CSV file with this mapping is created when the job is run. Only available if multiple receptors are selected from the Receptor option menu.

Set cutoff for clash detection text box

Specify the cutoff ratio used to identify a clash between atoms. The ratio is the distance between two atoms divided by the sum of their van der Waals radii, and a pair of atoms is counted as a clash when their ratio is below the cutoff. A smaller value therefore detects fewer clashes. The default is 0.75, and the value can range from 0 to 2.0.

Job toolbar

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

Job Server is required for submission of FEP+ Pose Builder jobs. To learn more about Job Server, see Job Submission to a Cluster.

The Job Settings button opens the 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

Related Topics