Protein-Protein Docking Panel

In this panel you can set up and run a job to dock a ligand structure to a receptor structure, where the ligand or the receptor can be a protein or a nucleic acid structure (DNA/RNA); dock an antibody to an antigen; or form a dimer of a single protein.

To open this panel: click the Tasks button and browse to Biologics → Protein-Protein Docking.

  • Using
  • Features
  • Additional Resources

Using the Protein-Protein Docking Panel

The Protein-Protein Docking panel provides an interface to the Piper program, licensed from Acpharis.

The basic algorithm is as follows. The ligand is rotated into a large number of different orientations with respect to the receptor, and each of the ligand orientations is translated to find the best docking score to the receptor. The top 1000 rotations are clustered using the RMS distance between matching atoms in each pair of rotated structures. The structure that is taken from each cluster is the one with the most neighbors in the cluster. After the docking is done, a refinement is performed by default on the side chains of residues within 5 Å of the interface, to minimize clashes and optimize interactions.

The structures you use should be properly prepared for docking, which mainly means that the structure must have hydrogen atoms. It also includes deleting or keeping het groups: these are included in the output structure if present when the structures are docked. You might want to keep ligands and cofactors but delete crystallization aids. See Preparation of Structures for Protein-Protein Docking for more information.

The preparation requirement is enforced when you import structures, and you are presented with a choice of a quick preparation or preparation in the Protein Preparation Workflow Panel if preparation has not been done. Although you can import structures directly from the PDB, these structures often have missing atoms, and the missing atoms are often in surface residues. If these residues are important for docking, you should consider running a side-chain prediction (click the Tasks button and browse to Biologics → Predict Side Chains) to ensure that the critical side chain atoms are present in the structures that you dock. You can include a side-chain prediction in the process of protein preparation in the Protein Preparation Workflow Panel.

The basic workflow is as follows:

  1. Choose the kind of system you want to dock, in the Mode section. You can dock antibodies to antigens and generate dimers as well as docking two general proteins or nucleic acid structures (DNA/RNA).

  2. Import or select the protein structures. This includes selecting the chains from the protein if it has multiple chains.

  3. Change settings for the ligand rotations and number of poses, if desired.

  4. Set constraints for residues in the structures to encourage docking in a particular region, if desired. See Attraction and Repulsion tab.

  5. Set distance restraints for residues in the structures to enforce docking in a particular region, if desired. See Distance Restraints tab and Protein-Protein Docking Distance Restraints.

  6. Start the docking job.

A typical docking job with the default parameters takes several hours on a single processor, so distributing the job over multiple processors (cores) reduces the turnaround time considerably. You can set the number of processors to use in the Job Settings dialog box.

The output structures have two properties, PIPER pose energy and PIPER pose score, which are shown in the Project Table. PIPER represents the interaction energy between two proteins with the following expression:

E = w1*Erep + w2*Eattr + w3*Eelec + w4*EDARS,

where wn are weights, Erep and Eattr are the repulsive and attractive contributions to the van der Waals interaction energy, and Eelec is an electrostatic energy term. This sum E is reported as PIPER pose energy. EDARS is a pairwise structure-based potential constructed by the ‘decoys as the reference state’ (DARS) approach, and it primarily represents desolvation contributions. The fourth term (w4*EDARS) is reported as the PIPER pose score. See ref. [17]

There are several possible next steps for a protein-protein docking job. To choose the next step from a suggested list, use the Workflow Action Menu for the results entry or entry group in the Entry List (Entries).

For example, after docking, you may want to refine the interface, which involves selecting the interface residues. An easy way to do this is to use the Quick Select tools. For a protein-protein interface, click the interface button . For an antibody-antigen interface, click the choose item button and select Antibody-Antigen.

To run protein-protein docking from the command line, you can use the following command. Run the command with -h for more information.

$SCHRODINGER/run -FROM psp piper.py

To write out input files, click the arrow next to the Settings button,

and choose Write (more...).

For information on command options, see piper.py Command Help.

You can also sort and rank the poses with the glide_sort utility, as illustrated by the following command:

$SCHRODINGER/utilities/glide_sort -r report.txt -o sorted.maegz -use_prop r_bioluminate_PIPER_pose_energy poses.maegz

The input docked poses are in poses.maegz; the output poses are in sorted.maegz. The report on the ranking is in report.txt. For information on the syntax, see glide_sort Command Help.

Protein-Protein Docking Panel Features

Mode section

Select the kind of protein-protein docking calculation you want to do from the options in this section.

  • Standard—Dock a ligand to a receptor. The ligand and the receptor can be protein or nucleic acid structures (DNA/RNA). This is the most general docking calculation that you can do.

  • Antibody—Dock an antibody to an antigen. You can choose whether to consider the non-CDR region with the option Mask non-CDR region. By default the non-CDR is masked, i.e. the attractive potential for residues in the non-CDR region is removed. The Chothia definition is used for the CDR region.

  • Dimer—Dock the protein to itself to form a dimer, subject to C2 symmetry constraints.

Structures to dock section

In this section, you specify the structures that you want to dock. For each structure there is an option menu, a text box to display the title of the structure, and a button to include the structure in the Workspace and zoom to it. The labels on the option menus depend on the docking mode that you selected.

  • Standard—The menus are labeled Receptor and Ligand. It doesn't matter which structure you choose for the receptor and which you choose for the ligand.

  • Antibody—The menus are labeled Antibody and Antigen. After prompting you to add missing hydrogens, the antibody is analyzed to locate the CDR regions and determine which are the light and heavy chains. A progress bar is displayed while the analysis is done. When the analysis finishes, another dialog box opens, prompting you to select the chains to use for the antibody (receptor). You must select two chains: a light chain and a heavy chain.

  • Dimer—The top menu is labeled Monomer, and the bottom menu is dimmed.

Each option menu has these items for selecting the source of the structure.

  • Browse for File—Opens a file selector so that you can browse to the location of the file and select it. The structure is imported into the project as a new entry, and added to the Workspace.

  • From the Workspace—Use the structure that is in the Workspace. You should ensure that only the desired structure is included in the Workspace. If you have just prepared the structure with the Protein Preparation Wizard, it should already be in the Workspace.

  • From Project Table—Use the structure that selected in Project Table or Entry List. You should ensure that only the desired structure is selected.

  • From PDB ID—Opens a dialog box in which you can specify a PDB ID. The protein you specify is imported from the PDB, either from a local copy or from the web site. It is added to the project and to the Workspace. Structures taken directly from the PDB without preparation are likely to have atoms missing.

The structures must be adequately prepared. If hydrogens are missing, you are prompted to add them. If the structure has multiple chains, you are prompted to choose the chains. You can choose more than one chain for the docking.

When the structure is imported from a file, it is added to the project and included in the Workspace. If the structure is removed from the Workspace you can add it with theInclude and zoom button (eye icon).

To view the sequences of the structures you imported in the Multiple Sequence Viewer/Editor Panel, click View Sequences.

Number of ligand rotations to probe box

Number of ligand rotations (orientations) to dock to the receptor. The default of 70,000 corresponds approximately to sampling every 5° in the space of Euler angles, and is the maximum value allowed. Decreasing the number of rotations generally degrades the results, but decreases the run time.

Maximum poses to return box

Maximum number of poses to keep .Each pose is the center of a cluster that results from clustering the top 1000 results of rigid docking of the ligand. If more clusters are found than the number of poses to return, the clusters are ranked by size and poses are chosen from the largest clusters. If fewer clusters are found than the maximum number of poses to return, one pose per cluster is returned.

Refine output poses option

Refine the output poses, to reduce the incidence of clashes between the two proteins. The refinement performs an OPLS4 force-field minimization (in vacuum) of the side chains of all residues within 5 Å of the interface. This option is selected by default. Refining the output poses significantly increases the time taken for the job, but reduces the incidence of clashes to a very small number (if not zero). You can use other refinement protocols from the command line—see piper.py Command Help.

Preserve archive of top 1000 unclustered poses option

This option will write a .maegz file containing the top 1000 unclustered poses in the Working Directory. This option is selected by default. The raw poses are not refined.

Attraction and Repulsion tab

In this tab you can define restraints on the docking process, by providing an additional attractive term to the potential, removing the attractive potential, or declaring residues to be buried, for residues that you select. Restraints do not guarantee that a residue will or will not participate in binding; rather they modify the potential function, to make binding to the residue easier or harder.

Add Restraint button

Add a restraint row to the table.

Restraints table

In this table you can define restraints on selected residues, to increase or remove the attractive potential, or change the repulsive van der Waals radius. The table columns are described below.

Type Choose the type of restraint to apply. The types are:
Attraction—Increase the attractive potential for participation in binding. The value in the Bonus column is added to the default value of 1 to define the scaling factor for the attractive potential.
Buried—Increase the van der Waals radius. The interaction includes attractive and repulsive vdW energy terms.
Repulsion—Set the attractive potential to zero. When calculating the energies, only the repulsive vdW energy term is accounted for, the attractive term is ignored.
Component Choose the protein or nucleic acid that the restraint applies to. The choices on the menu are the same as the labels on the option menus in the Structures to Dock section.
Actions This column has two action buttons, one for deleting the restraint, and the other for zooming in on the atoms that define the restraint.
Bonus Define the increase in the attractive potential for Attraction restraints. The value must be in the range 0.11 to 0.99. This value is added to 1 to define a scaling factor for the attractive potential.
Residues Lists the residues affected by the restraints, and provides tools to select the residues. If you click in a table cell in this column, you can choose from two sources of the selected residues:
From Workspace selection—Use the current Workspace selection to define the residues for the restraints.
Choose Workspace atoms—Open the Atom Selection Dialog Box, so you can select the residues for the restraints.
The selection you make is filled out to complete any residues that are only partly selected.
Distance Restraints tab

In this tab you can define distance restraints between residues to be applied during docking. You can define up to four groups of restraints; the restraints for each group must be satisfied (a logical AND between groups). Within each group you specify individual residue pairs and distances for a single restraint, and then decide how many of these restraints must be satisfied.

Restraints table

In this table you can define restraints between selected residues. The table columns are described below.

Receptor Chain Receptor chain for the restraint.
Receptor Residue Receptor residue that the restraint applies to.
Ligand Chain Ligand chain for the restraint.
Ligand Residue Ligand residue that the restraint applies to.
Minimum Distance Minimum distance in angstroms between the closest atoms in the ligand residue and the receptor residue. You can edit the distance value.
Maximum Distance Maximum distance in angstroms between the closest atoms in the ligand residue and the receptor residue. You can edit the distance value.
New Restraint button

Add a new restraint. Opens the Define New Restraint dialog box, in which you can define the ligand residue and the receptor residue for the and set the maximum and minimum distance. The residues can be chosen by picking in the Workspace, by using the Workspace selection, by using the Atom Selection Dialog Box, or by typing in the chain, residue name and residue number, e.g. A:GLY44. When you click OK, a new row is added to the table with the information given in the dialog box.

Delete and Delete All buttons

Delete the selected row from the table, or delete all the rows in the table.

Poses must satisfy options

Select an option for the restraints that must be satisfied, from those in the table.

  • All—all restraints in the table must be satisfied.
  • At least n—At least the specified number of restraints must be satisfied. When restraints are checked, the checking stops when the given number of restraints is satisfied.
Import and Export buttons

Import or export a set of distance restraints, as a CSV file. Opens a file selector to navigate to the desired location and name the file.

Job toolbar

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

The Job Settings button opens the Protein-Protein Docking - 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