Interaction Fingerprints Panel

Generate fingerprints for interactions between a receptor and a set of ligands, and use the fingerprints for similarity analysis and clustering.

To open this panel: click the Tasks button and browse to Biologics → Structural Interaction Fingerprints.
To open this panel from the entry group for the results of a Glide docking job, and load the results, use the Workflow Action Menu .

  • Using
  • Features
  • Additional Resources

Using the Interaction Fingerprints Panel

Interaction fingerprints are calculated as a set of bits for the presence or absence of particular types of interactions between a set of ligands and the active site residues of a receptor. The ligands can be small molecules (ligand docking), peptides (peptide docking), or proteins (protein-protein docking). The active site for this purpose is defined by distance cutoffs: any residue that has atoms within the specified cutoff distance from ligand atoms is included in the interacting set. You can change this definition in the Interaction Fingerprints — Advanced Settings Dialog Box, either by changing the cutoffs or by providing an ASL expression for the interacting residues.

The complexes can be defined in two ways: either a receptor followed by a set of ligands, or a set of ligand-receptor (or protein-protein) complexes. For the first, the receptor is chosen as the first entry in the Project Table that is selected, and the ligands are taken to be the remaining selected entries. So, for example, if you import a pose viewer file from Glide or a peptide docking run and select the entry group for that file, the selection fits the requirements. For the second, each selected entry must be a receptor-ligand complex. So for example, the output from an IFD calculation or a protein-protein docking run would meet these requirements. If different proteins are represented, you can align them by sequence using a multiple sequence alignment before generating the fingerprints. The proteins must have the same number of chains and be reasonably similar.

When you have generated the interaction fingerprints, you can examine them by displaying the interaction matrix (click Display Interaction Matrix). This display charts the interactions between each ligand and each interacting residue in the receptor, so you can see which residues have a particular kind of interaction with each ligand, or which ligands have a particular kind of interaction with a specific receptor residue.

The panel also provides some tools for using the fingerprints to examine ligand similarities based on the fingerprints, and to cluster the ligands by these similarities.

For a detailed description of the method and its uses, see Deng, Z.; Chuaqui, C.; Singh, J. J. Med. Chem.2004, 47, 337-44 and Singh, J.; Deng, Z.; Narale, G.; Chuaqui, C. Chem. Biol. Drug. Des.2006, 67, 5-12.

Interaction Fingerprints Panel Features

Tabs

  • Fingerprint Generation
  • Similarity
  • Cluster

Fingerprint Generation tab

In this tab, you choose the interactions to include in the fingerprints and generate the fingerprints. You can then examine the fingerprints by displaying the interaction matrix (ligands vs receptor residues), export them to file, or add fingerprint-derived properties to the Project Table.

Generate fingerprints from Project Table options

Specify the type of structure source that is being supplied from the Project Table selected entries.

  • Docked poses—The first entry must be a receptor and the remaining entries must be ligands, for example, a pose-viewer file from a Glide docking run or a peptide docking run.

  • Receptor-ligand complexes—Each entry must be a receptor-ligand complex, for example, the output from an induced-fit docking (IFD) calculation, where the ligand is a small molecule.

  • Protein-protein complexes—Each entry must be a protein that contains chains that serve as receptors and ligands, for example, the output from a protein-protein docking calculation. When you choose this option, an option menu is displayed below so you can choose the protein chains that define the receptor; the remaining chains define the ligand.

Analyze interaction of receptor chains option menu and bound to protein ligand chains text

Choose the chains that form the "receptor" from the option menu, by checking or clearing the boxes for the chains. The remaining chains form the "ligand", and are reported in the text to the right of the option menu (bound to protein ligand chains text). This item is only present if you select Protein-protein complexes.

This menu is populated from the chains present in the input structure. If more than one structure is specified, the chain names across all structures must be unique, otherwise the structures cannot be merged. You can rename the chains using the Change Atom Properties Panel.

Interactions to include list

Select the interactions that you want to generate fingerprints for. You can select multiple items with the usual control-click and shift-click.

  • Any Contact—A ligand atom is within the required distance of a receptor atom.
  • Backbone Interaction—A ligand atom is within the required distance of a receptor backbone atom.
  • Sidechain Interaction—A ligand atom is within the required distance of a receptor side chain atom.
  • Polar Residues—A ligand atom is within the required distance of an atom in a polar residue of the receptor (ARG, ASP, GLU, HIS, ASN, GLN, LYS, SER, THR, ARN, ASH, GLH, HID, HIE, LYN).
  • Hydrophobic Residues—A ligand atom is within the required distance of an atom in a hydrophobic residue of the receptor (PHE, LEU, ILE, TYR, TRP, VAL, MET, PRO, CYS, ALA, CYX).
  • Hydrogen Bond Acceptor—The ligand forms a hydrogen bond with an acceptor in a receptor residue.
  • Hydrogen Bond Donor—The ligand forms a hydrogen bond with a donor in a receptor residue.
  • Aromatic Residue—A ligand atom is within the required distance of an atom in an aromatic residue of the receptor (PHE, TYR, TRP, TYO).
  • Charged Residue—A ligand atom is within the required distance of an atom in a charged residue of the receptor (ARG, ASP, GLU, LYS, HIP, CYT, SRO, TYO, THO).

Polar hydrogen atoms are included when determining all interaction types. Nonpolar hydrogen atoms are not included by default, but can be included by selecting an option in the Advanced Settings dialog box. This dialog box also allows you set the distance cutoff for interactions and parameters for hydrogen bonds, as well as define the interacting residues in the receptor.

Align sequences (for different proteins) option

Align the sequences of the proteins when different proteins are represented in the complexes, using a selected protein as the reference. A multiple sequence alignment of all the proteins is performed before continuing. The proteins must have the same number of chains, and a reasonable degree of similarity between the chains.

Reference option menu

Choose the reference protein for the sequence alignment.

Advanced Settings button

Open the Advanced Settings dialog box, in which you can change the definition of the interacting region, the interaction distance cutoffs, and hydrogen bond definition cutoffs.

Generate Fingerprints button

Click this button to generate the fingerprints. A progress bar is displayed below this button.

Export Ligand Interaction Counts to Project Table button

Add the total number of interactions with the receptor for each interaction type as properties to the Project Table for each ligand.

Export to File button

Export the fingerprints to a CSV file or a Canvas fingerprints file. The title is exported along with the fingerprints to the CSV file by default. If you select Export non-fingerprint properties option in the Advanced Settings dialog box, all the properties in the Project Table are exported, including the entry ID.

Display Interaction Matrix button

Open the Interaction Matrix Dialog Box, in which you can view a plot that shows the presence of a chosen interaction as a function of residue number and ligand number, as well as a count of the interactions per ligand and per residue.

Similarity tab

In this tab you can calculate the similarity of one or more ligands to a set of ligands. The ligands that you want to use as references must be included in the Workspace, and the ligands for which you want to calculate similarities must be selected in the Project Table. You must generate fingerprints for all of these ligands before you calculate similarities: any ligands that don't have fingerprints are silently ignored.

Similarity metric option menu

Choose the metric that is used for calculating similarities. See canvasFPMatrix for a list of metrics and their definitions.

Tversky alpha and Tversky beta text boxes

Specify the alpha and beta parameters if the Tversky metric is chosen from the Similarity metric option menu.

Calculate Similarity button

Calculate the similarities. The similarities are reported as properties in the Project Table for the selected entries. If only one entry is included in the Workspace, the property name is Canvas metric Similarity. If more than one entry is included in the Workspace, five properties are added:

  • Canvas Mean metric Similarity—Average of similarities to all included entries
  • Canvas Max metric Similarity—Similarity of the most similar included entry
  • Canvas Min metric Similarity—Similarity of the least similar included entry
  • Canvas Max metric Similarity ID—the entry ID of the most similar included entry
  • Canvas Min metric Similarity ID—the entry ID of the least similar included entry
Sort selected entries by similarity option

Sort the selected entries in the Project Table by the similarity values, from highest to lowest. If you have more than one ligand in the Workspace, the maximum similarity is used for sorting.

Cluster tab

In this tab, you can cluster the selected entries by their similarity values, using the fingerprints and the settings in the Similarity tab. Hierarchical agglomerative clustering is used. Once clustering is done, you can examine the clustering statistics, a dendrogram of the clustering, and the distance matrix, and you can apply the clustering to the selected entries, to create groups or create index and size properties.

Linkage method option menu

Specify the linkage method. These are the methods used by Canvas for hierarchical clustering.

Calculate Clustering button

Perform the hierarchical clustering calculation.

Clustering Statistics button

Display a plot of various statistics of the clustering as a function of the number of clusters, in the Clustering Statistics panel. The statistics are: Kelley penalty, R-squared, Semipartial R-squared, Merge distance, Separation ratio. You can click in the plot to set the number of clusters in the Number of clusters text box.

Dendrogram button

Display a dendrogram of the hierarchy of clusters, in the Dendrogram panel. You can click in the plot to set the number of clusters in the Number of clusters text box.

Distance matrix button

Display the distance matrix used for clustering graphically, with values represented by a color map, in the Distance Matrix panel. You can display the matrix in cluster order (as shown in the Dendrogram panel) or in the original (input) order. You can click in the plot to display the 2D structures in the panel, and optionally in the Workspace.

Apply clustering section

In this section, you can apply the clustering to the selected entries in the Project Table for a particular number of clusters.

Number of clusters text box

Specify the number of clusters to use when applying the clustering results to the selected entries.

Create options

Specify the action to be taken when applying the clustering.

  • Duplicate entries to a new group for each cluster—Create new groups for each cluster, with titles set to Cluster N (or N_M if clustering has been applied M times), duplicate all the selected entries, and put the duplicates into these new groups.
  • Move entries to a new group for each cluster—Create new groups for each cluster with titles set to Cluster N (or N_M if clustering has been applied M times), and move the entries from their current location into the new groups.
  • A group containing the structures nearest the centroid in each cluster—Create a new group, entitled Representative Entries (with a suffix M if clustering has been applied M times) , and move the structure that is nearest the centroid in each cluster to this group.
  • Cluster index and size properties for each entry—Create two new properties for each entry that record which cluster the entry belongs to (the index) and how big the cluster is.
Apply Clustering button

Apply the clustering to the selected entries in the Project Table using the option chosen under Create.

Related Topics