Macrocycle Bioactive Conformation Propensity Panel

Evaluate the propensity of a macrocyclic compound to adopt a conformation similar to that adopted by a known active (non-cyclic precursor in a binding site).

To open this panel: click the Tasks button and browse to General Modeling → Macrocycle Propensity.

  • Using
  • Features
  • Additional Resources

Using the Macrocycle Bioactive Conformation Propensity Panel

This task requires a reference ligand and a set of macrocycles. The propensity for a macrocycle to adopt the same conformation as the reference ligand is determined by the RMSD of a set of atoms that are considered to be important for activity. This set of atoms must be part of a contiguous fragment, as it is represented by a SMARTS pattern, in which all of the atoms are used for the RMSD calculation. The SMARTS pattern can be generated from the Workspace structure, if you have either the reference ligand or a suitable one of the macrocycles in the Workspace. The macrocycle conformations can be generated as part of the job, or you can provide a pregenerated set of conformations.

The conformations are written to the output Maestro file, along with the RMSD in angstroms between the macrocycle conformation and the reference ligand for the specified set of atoms (in the property stabilization rmsd).

The results of the evaluation are reported as two properties that apply to the ensemble of conformations for a given macrocycle. These properties are added to each conformation of the macrocycle.

  • stability metric expval, which is calculated by weighting the RMSD value for each conformation by the Boltzmann probability for that conformation, and summing this product for all conformations. The Boltzmann probabilities are based on the Prime Energy values, and are calclated at 298.13K.

  • stability prob metric below thresh, which is the probability of finding conformations with an RMSD of less than X, where X is specified in this panel. This is the sum of the Boltzmann probabilities over conformations for which the RMSD is less than X. The threshold X is also recorded as a property (stability thresh) and added to each conformation.

Macrocycle Bioactive Conformation Propensity Panel Features

Macrocycles section

Specify the source of the macrocycles and the method for sampling macrocycle conformations.

Use macrocycles from option menu

Choose the structure source for the macrocycles.

  • 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.
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.

Sampling options

Select an option for sampling the macrocycles:

  • Perform macrocycle sampling—run a macrocycle sampling job to generate macrocycle conformations. Click Options to set options for the sampling procedure. A panel opens that allows you to set the same options as are available in the Prime Macrocycle Sampling Panel.

  • Macrocycles are pre-sampled—select this option if you are providing a set of previously sampled macrocycle conformers.

Reference Ligand section

Specify the source of the reference ligand and define the criteria for the comparison of the macrocycles with the reference ligand.

Use reference from option menu

Choose the structure source for the reference ligand.

  • Workspace (included entry)—Use the entry that is currently included in the Workspace. Only one entry must be included in the Workspace.
  • File—Use the specified file. When this option is selected, the File name text box and Browse button are displayed.
Open Project Table button

Open the Project Table panel, so you can include 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.

SMARTS text box and Get from Workspace Selection button

Specify the atoms that are common to the reference and the macrocycles and are considered important for activity, as a SMARTS pattern. These atoms are used to calculate the RMSD between the reference and macrocycles. You can pick the atoms in the Workspace and click Get from Workspace Selection to generate a SMARTS pattern for the atoms. The atoms must all be part of a single, connected fragment.

If you chose File as the structure source for the reference ligand, you can place one of the macrocycles in the Workspace to generate a SMARTS pattern for the common atoms; otherwise you will have to import the reference ligand or type (or paste) in the SMARTS pattern.

Report probability of finding a pose below X RMSD option and text box

Report the probability of finding a pose below the specified RMSD of the selected atoms based on a Boltzmann-weighted ensemble of the macrocycle conformations. High values correspond to low ring strain for a macrocycle.

Job toolbar

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

The Job Settings button opens the Macrocycle Bioactive Conformation Propensity - 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