[ Refinement | Multiple Receptor Conformation Docking | Explicit Group Docking ]

The standard ICM docking procedure desribed in the previous section incorporates a flexible ligand and a semi-rigid receptor wherby flexibility is incorporated by including soft van der Waals potential maps. However due to ligand induced-fit there is sometimes a need to incorporate flexibility into the docking. There are three ways to do this in ICM:

• Ligand and receptor complex refinement. This approach allows the side-chains of the receptor to be fully flexible.
• Multiple receptor conformation docking. Multiple receptor conformations can be obtained from modeling alternative conformations or from an ensemble of crystal structures.
• Explicit group docking allows certain defined residues to be flexible during the docking procedure. For example the hydroxyls of Ser, Thr, and Tyr can be treated explicitly during docking and the rest of the atoms will be treated as maps.

18.2.1 Ligand and Receptor Complex Refinement

To undertake flexible ligand and receptor refinement docking you first need to dock the ligand into the receptor using the procedures described in the previous section entitled Small Molecule Docking. The next step is to select the pose from your docking experiment you wish to use for flexible docking.

• Docking/Flexible-Receptor/Refinement and a window as shown below will be displayed.
• Enter the name of the initial docking project.
• Select the answers.ob file from the docking experiment.
• If you docked more than one ligands you need to select which ligand you want to use for the flexible receptor docking. For example if you want to refine the 3rd ligand in your docked database you would enter 3 in the Object number data entry box.
• Select which member of the stack of docking solutions you wish to use. In most cases it will be the first member of the stack and therefore you will enter "1".
• Enter a name for the refined complex.
• You can display the run in the graphical display but this will slow the process down.

18.2.2 Multiple Receptor 4D Docking

Additional Resources: Tutorial: 4D Docking to Multiple Conformations of a Flexible Loop in the Aldose Reductase Ligand Binding Pocket

How to generate a stack of conformations for a single crystal structure:

One way to do this is to select a number of side-chains and right click on the graphical selection and choose Advanced/Optimize Side Chains or right click on the ligand in the binding pocket and select Advanced/Optimize Ligand Vicinity. Or you can model the loop regions using MolMechanics/Sample Loop.

How to generate a stack from an ensemble of crystal structures: {Ensemble of Crystal Structures}

Step 1: Read into ICM the ensemble of crystal structures.

Step 2: Convert the most complete crystal structure into an ICM object. Make this object the current object (Right click in workspace and select Set to current).

Step 3: Add the conformation to the object's conformational stack.

Step 4: Notice the new stack is inside the object. This is an object stack and not a global stack. Therefore this object stack is protected if you do any other MC simulation.

Step 5: Impose the confromation of one of the other crystal structures onto the icm object.

Step 6: Store new imposed conformation in the object stack and then repeat Step 4 and 5 for all crystal structures in the ensemble. Once finished setup the docking project in the standard way but before generateing the maps select Flexible Receptor / Setup 4D grid.

How to Start the 4D Docking Procedure

• Setup the docking Project (Docking/Set Project) and setup the receptor (Docking/Setup Receptor - check the option not to make maps) as described in the Small Molecule Docking section.
• Before generating the maps you need to select Docking/Flexible Receptor/ Setup 4D grid.
• Make the maps (Docking/Re-make Receptor Maps)

• Move the embedded stack in the original object to a global stack

load stack a_

• Move the global stack into the docking receptor object.

store stack a_3. #if the _rec object is the third object.

18.2.3 Explicit Group Docking

Additional Resources: Tutorial

• Setup the docking as described in the Small Molecule Docking section.
• Before making maps choose Docking/Flexible Receptor/Explicit Groups