Combine Fragments Panel

In this panel you can set up and run jobs that attach a set of pre-positioned fragments, either to each other or to a defined core-containing molecule.

To open this panel, do one of the following:

  • Click the Tasks button and browse to Enumeration and Ideation → Combine Fragments
  • Click the Tasks button and browse to Ligand Preparation and Library Design → Enumeration → Combine Fragments
  • Using
  • Features
  • Additional Resources

Using the Combine Fragments Panel

The Combine Fragments panel allows you to run a job to join fragments that are pre-positioned with respect to each other, for example by docking into a receptor site. The fragments can either be joined directly to each other ("direct joining") or they can be joined to defined core-containing molecules ("core linking").

The fragments are joined by identifying bonds that can be formed between the fragments, or the fragment and the core-containing molecule. The bonds are identified by two criteria:

  • The angle between the bond directions must be less than a threshold. The default is 15°. This criterion ensures a proper rotational alignment of the fragments .
  • The distance between the atom that remains in one fragment and the atom that leaves in the other fragment must be less than a threshold (after adjustment of the bond lengths in each fragment to the ideal bond length for the new bond). The default is 1 Å. This criterion ensures a proper translational alignment of the fragments.

The fragments can overlap, and both internal and peripheral (H and halogen) bonds can considered for breaking to form a bond with another fragment. However, if the distance between the fragment centroids is below a given (settable) threshold, the fragments are not joined: they are considered to occupy the same location in the receptor.

The thresholds can be set in the Combine Fragments - Advanced Options Dialog Box.

Direct linking of fragments is done in several rounds. The first round attempts to join pairs of fragments. In the second round, the results of the first round are used as input, so that the results can be combinations of up to four fragments, and so on.

For fragments that have no atoms that are close enough to create new bonds but are still not far apart, methylene linkers are included to assess whether a bond can be formed. One methylene is added to each fragment; thus two fragments can be joined by at most two methylene linkers.

In core linking, the fragments are joined in turn to each core molecule, but are not joined to each other, and no methylene linkers are included. A minimum and a maximum number of fragments to attach to each core can be set; the defaults are 2 and 4. The bonds considered for linking in the core molecule are all terminal bonds (carbon-hydrogen and carbon-halogen). Since there is potentially a large number of combinations, the fragments are randomly sampled in a number of trials, with no repetitions between trials. The number of trials can be set; the default is 20.

Once the fragments are combined, the resultant structures are passed through a minimization in which all heavy atoms in the fragments are restrained with a restraint of 100 kcal/mol. No restraints are placed on core molecules or linker atoms.

Combine Fragments Panel Features

Use ligands from input controls

Specify the source of the ligands (fragments) by choosing an item from the option menu. The choices are Project Table (selected entries) and File. If you select File, the Input file text box and Browse button become available, and you can enter the file name in the text box or click Browse and navigate to the file. The file must be in Maestro format.

Use ligands from option menu

Choose the structure source for the fragments to combine.

  • 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.
  • File—Use the specified file. When this option is selected, the File name text box and Browse button are displayed. The allowed file types are: Maestro.
Open Project Table button

Open the Project Table panel, so you can select 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. The allowed file types are: Maestro.

Joining method section

Choose the method for joining the fragments, from the following options:

Direct joining option and controls

Select this option to join the fragments directly to each other (with the possible addition of 1 or 2 methylene linkers). When the option is selected, you can specify the number of rounds that are run when trying to join the fragments. Fragments are joined in pairs in each round, and the output of each round is the input for the next round, so that you can join multiple fragments.

You can also select Check for VDW clashes before joining to check whether there is any overlap between the fragment atoms based on their van der Waals radii before joining the fragments. If this option is selected, fragment combinations that have clashes are skipped.

Linking option and controls

Select this option to join the fragments to one or more core-containing molecules. These molecules are specified by entering a file name in the Core file text box, or clicking Browse and navigating to the file. All molecules in the file are used as cores.

Attachment bonds section

In this section you specify the attachment bonds on the fragments: the bonds that are broken and then joined to another fragment or to a core.

  • All hydrogens and halogens—Use all bonds to hydrogen atoms and halogen atoms as attachment bonds.

  • SMARTS patterns—Limit the bonds to hydrogens and halogens that can be used as attachment bonds to those that match the specified SMARTS patterns. If you select this option, the controls below it become available:

    Pattern text box

    Enter a SMARTS pattern in this text box to define an allowed attachment bond.

    Get From Selection button

    Click this button to load the Pattern text box with a SMARTS pattern for the atoms that are selected in the Workspace. There must be atoms selected in the Workspace for this button to be available. Once the pattern is in the text box, you can edit it before adding it to the table.

    Add button

    Click this button to add the SMARTS pattern in the text box to the table.

    Remove button

    Select SMARTS patterns in the table, then click this button to remove the patterns from the table.

    SMARTS table

    Lists the SMARTS patterns that will be used to limit the attachment bonds. You can select multiple table rows with shift-click and control-click, and delete them with the Remove button.

Minimize section

Select the Minimize option to perform a partial or complete minimization of the joined structure. The section contains two options, one to minimize only the joined atoms and all the terminal (hydrogen and halogen) atoms, and the other to minimize all atoms.

If minimization is performed and Check for VDW clashes before joining is not selected, LigPrep is run with the option to untangle the structures, and discards any that can't be untangled. This process can increase the time taken by an order of magnitude, so a warning dialog box opens when you start the job with these conditions, giving you the opportunity to change the options.

Maximum output structures text box

Specify the maximum number of output structures from the possible combinations of fragments or of fragments and cores. The default is 10.

Advanced Options button

Opens the Combine Fragments - Advanced Options Dialog Box, in which you can set options for core linking and options that filter out combined fragments that have poor geometries or too many atoms.

Job toolbar

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

The Job Settings button opens the Combine Fragments - 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.

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