Induced Fit Docking Panel

This panel allows you to set up a sequence of jobs in which ligands are docked with Glide, then Prime Refinement is used to allow the receptor to relax, and the ligands are redocked into the relaxed receptor with Glide.

To open this panel, click the Tasks button and browse to Receptor-Based Virtual Screening → Induced Fit Docking. A dialog opens, giving the choice of this panel or the IFD-MD panel: clicking the button opens the panel, There is also an option to remember the choice and open the chosen panel directly in future.

  • Using
  • Features
  • Additional Resources

Using the Induced Fit Docking Panel

The Induced Fit Docking protocol aims to improve the docking of ligands in which it is believed that the receptor adjusts significantly to the presence of the ligand. The protocol performs a constrained minimization of the receptor followed by initial Glide docking of the ligands using a softened potential. A select set of the docked poses is passed on to Prime for a refinement step. After a Prime side-chain prediction and minimization, the best receptor structures for each ligand are passed back to Glide for redocking of the ligand.

There are actually two protocols, a standard protocol (the original protocol) and an extended sampling protocol (introduced in the 2013-1 release). A third, more automated and extensive protocol, is available in the IFD-MD Panel.

The standard protocol involves manual selection of a limited set of options for preparing the receptor to accommodate the ligand in the initial docking stage, by trimming residues. It also provides a choice of Glide precision in the final docking stage.

The extended sampling protocol handles the receptor preparation in an automated fashion, choosing the residues to trim and setting atom-specific van der Waals scaling factors on the basis of solvent-accessible surface areas, B-factors (if present), the existence of salt bridges, rotamer searches. The initial docking stage generates a large number of poses, which are clustered and filtered to produce up to 80 poses per ligand to pass to the Prime stage. The scoring of the final docked poses is based on Glide SP, so there is no need to select the Glide precision.

The Induced Fit Docking panel collects the relevant controls for each part of the protocol, with judicious selection of defaults for options that are not presented in the panel.

Preparation of the receptor structure prior to its use with the protocol is essential for good results. The requirements and a procedure for preparing the protein are described in the Induced Fit Docking User Manual — Contents.

The output structures are returned in a compressed Maestro file named jobname-out.maegz in the launch directory. The output poses include the IFDScore. property. In the Standard protocol, this score is the sum of the GlideScore from the redocking step and 5% of the Prime energy from the refinement calculation. In the Extended Sampling protocol, this score is based on the Glide SP descriptors.

To set up an induced fit docking calculation:

  1. Select the source of the ligands to be docked from the Ligands to be docked option menu. The ligands must be properly prepared (for example, by using LigPrep). Macrocycles may not be used as ligands. You can dock ligands from a file or from the Project Table. To dock ligands from a file, specify a file name, or browse to the ligand file, which must be a Maestro format file, compressed or uncompressed.

  2. Set up the receptor grid in the Receptor tab. For this purpose, the receptor must be displayed in the Workspace, with or without the ligand. If a ligand is not displayed, you must use define the center of the enclosing box in terms of receptor residues. The protein must be properly prepared for a Glide calculation.

  3. (Optional) Set up constraints. You can set up hydrogen bonding and metal constraints to the receptor with either protocol, and core constraints with the Extended Sampling protocol. The atoms you pick for H-bond and metal constraints must be H atoms on H-bond donors or H-bond acceptor atoms, or metal atoms. The constraints that you select are all applied during docking. You can also choose the stages in which to apply the constraints. Core constraints are applied in all stages.

  4. Select conformational sampling options in the Ligands tab.

  5. For the Standard protocol, set the initial docking options in the Glide Docking tab. The tasks in this tab are to perform protein preparation, remove residue side chains (by mutating temporarily to alanine) that might move in the real system, scale the van der Waals radii if necessary, select the docking mode, and decide how many poses to keep per ligand. The defaults represent reasonable choices.

  6. Select the residues that are refined in the Prime Refinement stage. You can add residues that you know to be important, even if they don't lie within the specified distance of the ligand – for example, the remainder of a loop that moves when the ligand binds. You can also select residues that should not be refined, such as those bound to a metal ion.

  7. For the Standard protocol, set the energy threshold and the the number of poses to keep in the Glide redocking step, and the docking accuracy (SP or XP). This step is expensive because a new grid is generated for each input structure. Setting tight thresholds will reduce the cost, and is especially desirable for XP docking.

  8. Set job options in the Jobs tab. If you want to distribute the Prime and Glide jobs, enter the number of CPUs for each. When you start the job, make sure you select a multiprocessor host.

  9. Enter a job name in the Job name text box, and click Run, or choose Job Settings from the Settings button menu,

    choose the host and set the job name in the Job Settings dialog box, and click Run.

When the job finishes, the final poses with their scores are written to a Maestro file in the job launch directory, named jobname-out.maegz. You can view the results in Maestro by importing the file. The final IFDScore score for each pose in the Standard protocol is calculated as the GlideScore plus 1/20th of the Prime energy. The IFDScore score in the Extended Sampling protocol is based on Glide SP descriptors.

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 ifd Command Help. This is useful if you want to change any of the options for which controls are not provided in this panel. See the Induced Fit Docking User Manual — Contents for information on the keywords in the input file.

Induced Fit Docking Panel Features

Ligands to be docked option menu

Choose the structure source for the ligands to dock.

  • 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.

Protocol option menu

The Induced Fit docking panel offers more than one protocol for performing calculations. These are available from the Protocol option menu. The choice of protocol controls the options that are displayed in the panel. The available protocols are:

  • Extended Sampling—Use the extended sampling protocol. When you choose this option, the Glide Docking and Glide Redocking tabs are hidden, as the controls in these tabs are not relevant to this protocol.

  • Standard—Use the standard (original) protocol.

  • Receptor
  • Constraints
  • Ligands
  • Glide Docking
  • Prime Refinement
  • Glide Redocking
  • Jobs

Receptor Tab

In this tab you set up the receptor grid. The receptor must be displayed in the Workspace.

Box center options and controls

These options provide two ways of specifying the center of the grid box.

  • Centroid of Workspace ligand— This option centers grids at the centroid of the ligand molecule. Select Pick and pick the ligand in the Workspace. Use this option if the receptor has a ligand that you can use to define the grid center.

  • Centroid of selected residues— This option centers grids at the centroid of a set of residues that you select. This allows you to define the active site with only the receptor in the Workspace. Click Specify Residues to open the Select Centroid Residues Dialog Box and select the residues.

The inner box is drawn in green and the outer box is drawn in purple after you have specified the center of the box.

Box sizeoptions and controls

Select an option to determine the size of the grid box:

  • Dock ligands similar in size to Workspace ligand—Select this option to automatically determine the size of the grid box. If the Box center option is Centroid of Workspace ligand, the enclosing box size is calculated automatically from the size of the ligand. If the Center option is Centroid of selected residues, the enclosing box size is set to a cube with sides of length 26 Å.

  • Dock ligands with length <= N Å—Select this option to set the size of the grid box. Enter the desired side length in the text box, in angstroms. The grid box has sides of equal length given by the value in the text box.

Constraints Tab

In this tab you can set up constraints to the receptor or to a ligand core position. All of these constraints are used when docking the ligand. The receptor must be displayed in the Workspace to set the constraints.

This tab offers the choice of hydrogen bond constraints, metal constraints, and core constraints. If you want to use any other types of constraints, you can write out the input file, and then use Glide keywords to specify other constraints.

H-bond/Metal section

In this section you can pick atoms in the receptor to create H-bond and metal constraints.

H-bond and metal constraint atoms text box and Pick option

Select Pick and pick receptor H-bond donor (H atoms) or acceptor atoms, or receptor metal atoms, in the Workspace to define Glide H-bond or metal constraints. The picked atoms are listed in the text box. Picking an atom a second time removes it from the list. The constraints are all applied to the docking stages that are chosen for constraint. Symmetry-related atoms (such as the other O atom in a carboxylate group) are automatically included as constraints, so you only need to pick one.

The constraints are applied using the default feature sets for hydrogen-bond donors and acceptors, and metal atoms. For more information on H-bond and metal constraints in Glide, see the Constraints tab in the Receptor Grid Generation Panel topic.

Docking stages in which to apply constraints option menu

Choose the Glide docking stages in which to apply the constraints, from Both, Initial, or Redocking.

Core section

In this section you can define a core constraint that restricts the docking to within a specified RMSD tolerance of a reference ligand.

Restrict docking to reference position option

Restrict the docking of ligands so that the ligand "core" lies within a specified RMSD of the core in the reference ligand. The core is defined in terms of a set of atoms or a SMARTS pattern; if the ligand does not contain these atoms, it can be skipped. This option must be selected to apply the core constraint, and to make settings for the core constraint.

There are two choices for the reference ligand.

  • Reference file—Use a structure in a specified file as the reference ligand. Click Browse to navigate to the file and select it. The file name is entered in the text box, and can be edited. You must ensure that the structure in the file is positioned properly with respect to the receptor.

  • Use existing docked ligand—Use the current pose of the ligand to be docked as the reference ligand. This option ensures that the docked pose does not deviate too much from the initial pose.

You can enter a tolerance for the RMSD in angstroms for restricting the docking to the reference position in the Tolerance text box.

Options for defining the core atoms

The options for defining the core atoms are listed below.

  • Maximum common substructure—the core atoms are determined for each ligand independently from the maximum common substructure of the ligand and the core-containing molecule.

  • All heavy atoms—the core atoms are all non-hydrogen atoms in the core-containing molecule.

  • All atoms—the core atoms are all atoms from the core-containing molecule.

  • SMARTS pattern—the core atoms are defined in terms of a SMARTS pattern. You can pick atoms in the Workspace and click Get From Selection to define the SMARTS pattern, or you can type a SMARTS pattern into the text box. The atoms in the core-containing molecule that match the pattern are marked in the Workspace with green markers.

Ligands Tab

In this tab you specify options for conformational sampling of the ligands.

Dock rigidly option

Dock the ligands as they are in the input file, without doing any conformational (torsional) sampling. This option is useful, for example, if you want to pregenerate the ligand conformers, or if you want to dock a native ligand in its native conformation.

Sample ring conformations option

Sample the conformations of rings. These conformations are not sampled in the conformation generation, which focuses on sampling of rotatable bonds, leaving the core fixed. This option is selected by default. Deselect this option if you want rings to remain in their input conformations throughout docking.

Energy window text box

Discard ring conformations whose energy is higher than that of the lowest conformation by the specified amount.

Amide bonds option menu

This option menu provides a choice of how to treat amide bonds. The choices are:

  • Penalize non-planar conformation—penalize amide bonds that are not cis or trans (default)
  • Vary conformation—allow nonplanar amide bonds
  • Retain original conformation— freeze amide bonds in their input conformation throughout docking
  • Allow trans conformation only—enforce trans conformation within a small angle range (20°)
Enhance planarity of conjugated pi groups option

Increase the torsional potential around bonds between atoms whose geometry should be planar (i.e. sp2 atoms). This option should make aromatic rings, amides, esters, and so on, less likely to adopt a nonplanar geometry. The Amide bonds options can also promote planarity, but if you want to improve planarity in the final docking stage, you should select this option.

Glide Docking Tab

In this tab, you set up the initial docking stage. This stage is intended to generate poses that can dock to the receptor when it adjusts to the presence of the ligand. To do this, side chains can be removed and interactions with hydrophobic groups can be adjusted to allow more room for the ligand.

This tab is disabled for the Extended Sampling protocol, as it is not relevant. It is available for the Standard protocol.

Protein preparation constrained refinement option

Select this option to perform the constrained refinement stage of the Protein Preparation procedure (see the Protein Preparation Workflow Panel topic). The constrained minimization ends when the RMSD is 0.18 Å or less. If you have already run the Protein Preparation Workflow for your receptor, you do not need to select this option. It is recommended that you run the Protein Preparation Wizard instead of relying on this option, and a warning is posted if the receptor does not appear to have been processed by the Protein Preparation Wizard. This option is deselected by default.

Trim side chains option and controls

Select Trim side chains if you want to temporarily remove side chains of residues before docking. These residues are temporarily mutated to alanine, and restored to the original in the Prime Refinement stage. The removal of side chains is important if the side chains move significantly upon docking, if there is more than one binding mode, or if there were problems in the PDB structure.

There are two options for trimming the side chains:

  • Automatic (based on B-factor)—Selects up to 3 residues that are within 5 Å of the ligand and have the highest B-factors; the B-factors must be above 40.
  • Manual—Select the residues manually. Click Specify Residues to open the Select Trim Sidechains Residues Dialog Box and select the desired residues.

Some situations in which you would want to choose residues for mutation are described below.

  • If the protein is apo and there are existing holo proteins, superimpose the apo structure on one of the holo proteins and select residues in the active site that adopt significantly different positions.
  • If there are side chains with alternate positions (colored green on PDB import) or have missing density (colored red on PDB import), and either are within 5 Å of the ligand, they should be included in the side chain mutation.
  • If there are multiple structures in the unit cell (that have been independently solved in the X-ray structure determination, for example), superimpose these structures with the Protein Structure Alignment panel (Tools menu), and look at the active site residues. Any residues for which the side chains are in different locations should be considered for mutation.
  • Any side chain with a temperature factor (B) greater than about 40 should be considered for mutation, but not if the whole structure has high B values. If the whole structure has high temperature factors, then rank the residues in order of decreasing temperature factors and chose from the top of this list until a maximum of 3 residues is chosen. You can do this automatically by selecting Automatic based on B-factor for Trim side chains.
Receptor van der Waals scaling text box

Specify the scaling factor for the receptor van der Waals terms. For more information on the scaling, see the Receptor tab in the Receptor Grid Generation Panel topic. The default value of 0.50 was chosen to permit enough flexibility for the ligand to dock in the best poses. If side chains are trimmed, this value is changed to 0.70. The binding-site residue mutation is expected to reduce the need to soften the receptor potential by van der Waals radii scaling.

Ligand van der Waals scaling text box

Specify the scaling factor for the ligand van der Waals terms. For more information on the scaling, see the Ligand Docking Panel DEPRECATED topic. The default value of 0.50 was chosen to permit enough flexibility for the ligand to dock in the best poses.

Maximum number of poses text box

Enter the maximum number of poses per ligand to retain from the initial docking. These poses are passed to Prime for the Prime refinement step.

Prime Refinement Tab

In this tab, you set options for the refinement of the protein to adjust to the poses of the ligand. The main task is to select the residues to refine. In general, you should choose residues for refinement that are within 5 Å of the active site, which is the default. To these you should add residues beyond this limit that have large motion—for example, if they are part of a helix or loop that goes close to the active site.

It is usually not necessary to exclude residues from refinement. If you are confident that the side chains are fixed— for example, if they are bound to a metal ion—you could leave these residues out of the refinement. In the case that there is a metal ion in the active site, the protein side chains that are ligating the metal should be excluded from the refinement.

Refine residues within N Å of ligand poses text box

Set a distance from the ligand for selecting residues to refine. Residues that have any atoms within the specified distance of any ligand atom are included in the refinement.

The default, 5.0 Å, is recommended, but values ranging from about 4 – 8 Å are reasonable to try. Jobs will run faster with smaller values but the results may not be good if significant side-chain movement is necessary to accommodate the new ligand.

Optimize side chains option

Include side chains in the Prime refinement (the default). If this option is deselected, only the minimization of the residues and ligand is performed, and not the side-chain optimization. Not optimizing side chains makes the calculations considerably faster. This option is only present for the Standard protocol, as side chains are always optimized in the current protocol.

Apart from speed, you might want to deselect this option if you are confident that the side chain conformations are essentially correct, or want to relax the structure without risking putting the side chains in new, and possibly incorrect, conformations.

Additional residues to refine text box and Specify Residues button

Select additional residues for refinement (such as a loop that must adjust to the presence of the ligand) that are outside the refinement cutoff. Click Specify Residues to open the Add Prime Refinement Residues Dialog Box, and select the residues to refine.

Do not refine residues text box and Specify Residues button

Select residues to leave out of the refinement that are inside the refinement cutoff. Click Specify Residues to open the Skip Prime Refinement Residues Dialog Box, and select the residues to leave out of the refinement.

Use implicit membrane option and Set Up button

Select this option to use the Prime implicit membrane model for all Prime calculations. If the Workspace structure does not already have a membrane model, click Set Up to open the Prime Membrane Setup Panel and set up the membrane. For more information, see Setting Up an Implicit Membrane. This option is only present for the Standard protocol.

Glide Redocking Tab

In this tab, you select the receptor-ligand complex structures that are used for redocking, and set options for the redocking of the ligands into the refined receptors.

In the redocking, a small number of extra conformations are generated, to improve the final pose. This is done by default; if you want to turn it off, remove the MULTI_LIG_CONF keyword from the input file, and then run the job from the command line.

This tab is disabled for the Extended Sampling protocol, as it is not relevant. It is available for the Standard protocol.

Redock into structures within N kcal/mol of the best structure and within the top M structures overall text boxes

Set a threshold for eliminating high-energy structures from the Prime refinement step and a limit on the number of structures. Structures whose Prime energy is more than the specified amount above the lowest-energy structure and are not among the lowest M structures are eliminated.

Precision options

Select SP or XP docking precision. For more information on the docking precision, see the Ligand Docking Panel DEPRECATED topic.

Extra-precision Glide docking is recommended only when you are redocking a small number of low-energy structures. To ensure that this is the case, you can make the redocking energy window N smaller than the default, reduce the maximum number of structures M to be redocked, or both.

Jobs Tab

This tab allows you to set options to run in distributed mode and to control how subjob failures affect the job.

Terminate job immediately if any subjob fails option

Terminate the entire job if any of the subjobs fails. This forces termination of any other subjobs as well. Results are returned for completed subjobs. By default, the job continues. When a job fails, you can restart it from the command line—see The ifd Command.

Number of Glide CPUs text box

Enter the number of CPUs for the Glide stages of the process. The Glide docking jobs will be distributed over the number of CPUs specified. In the initial docking, the number of subjobs cannot be greater than the number of ligands. In the redocking, each receptor-ligand complex is redocked in a separate Glide job.

Number of Prime CPUs text box

Enter the number of CPUs to be used by Prime. The Prime jobs will be distributed over the number of CPUs specified. Each receptor-ligand complex is refined in a separate Prime job.

Job toolbar

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

The Job Settings button opens the Induced Fit 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.

Related Topics