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Frequently asked questions regarding small molecule and protein-protein docking.

• What are the units of the energy values displayed after docking?
• I do not have ICM-VLS but I would like to calculate the binding energy of my docked complex - how can I do this?
• How do I sample conformations of flexible rings in docked ligands, for example, a "chair-boat" transition?
• How can I guide my docking to a known conformation of a smilar ligand?
• How do I reload a docking project?
• During a Virtual Ligand Screening experiment how many times should I re-run the docking?
• Which score value should I use for analysis?
• Some compounds are missing from my HITLIST.
• What constitutes a good docking score?
• When I view my docking run my ligand never jumps into the box - what did I do wrong?
• How do I identify the binding pockets in my receptor?
• How long does it take to dock one ligand using ICM-VLS?
• What does thoroughness mean?
• When I setup the receptor I am asked to move a probe - what is this?
• I want to dock to the receptor and include other molecules in the receptor such as a tightly bound water molecule - how can I do this?
• How can I run docking with a flexible receptor?
• How can I run the docking simulation from the UNIX command line?
• I have a complex I wish to generate an ICM VLS Score for, however I did not dock it using VLS. How can I do this?
• Why is there always a small difference between the score calculated interactively by scanScoreExternal and that obtained by docking (VLS)?
• How do I monitor and terminate a background docking job?
• How do I sample flexible ring conformations (boat, chair etc..) during docking?
• I am docking a racemic compound how can I sample both R and S states during docking?

21.5.1 What are the units of the energy values displayed after docking?

The energy units are kcal/mol

21.5.2 I do not have ICM-VLS but I would like to calculate the binding energy of my docked complex - how can I do this?

For more in depth information on this topic please see the command line manual www.molsoft.com/man however the basic approach is this: Calculuate the energy of the receptor (e1, a_1), energy of the ligand (e2, a_2) and the energy of the complex (e12) then the binding energy = e12 - e1 - e2

Here is a script to do this whereby the ligand is a_2 and the receptor is a_1:

electroMethod="boundary element"

surfaceMethod="constant tension"

surfaceTension=0.020

dielConst = 12.7

set terms "sf,el,en"

read object s_icmhome+"2ptc"

show energy a_1 a_1 mute

e1  =Energy("el,sf,en")

show energy a_2 a_2 mute

e2  =Energy("el,sf,en")

show energy mute

e12 =Energy("el,sf,en")

print "Binding energy = ", e12 - e1 - e2 

There are many different approaches to the evaluation of binding energy. One of the reasonable approximations has the following features: van der Waals/hydrogen bonding interaction is excluded since it has close magnitudes for protein-protein and for protein-solvent interactions; electrostatic free energy change is calculated by the REBEL method (see also the section "How to calculate the electrostatic free energy ... ") above); side-chain entropy change is calculated by standard ICM entropic term based on exposed surface area of flexible side-chains; hydrophobic energy change is calculated using surface term with constant surface tension of 20. cal/Angstrom.

21.5.3 How do I sample conformations of flexible rings in docked ligands, for example, a "chair-boat" transition?

Find your docking project file ( yourDockingProjectName.tab ) and set the ringFlexibilityLevel to 1 or 2.

In GUI, this parameter can be reset in the "Docking Preferences" dialog. It is called "Flexible ring sampling level".

21.5.4 How can I guide my docking to a known conformation of a smilar ligand?

Use Docking/Template as described here.

21.5.5 How do I reload a docking project?

To reload a docking project.

/Docking/Set Project - Type in the Docking Project Name (Case Sensitive)

Now you can browse scan solutions etc.... and use the maps to dock another ligand.

21.5.6 In a VLS run how many times should I run the docking?

Generally we suggest the docking should be repeated 2-3 times and the lowest ICM score pose should be taken.

21.5.7 Which score value should I use for analysis.

The value under the heading SCORE relates to the ICM docking score and is the best one to use for docking result analysis. The other score we provide - potential of mean force score (mfscore - http://www.molsoft.com/man/terms.html#term-mf) provides an independent score of the strength of ligand-receptor interaction.

21.5.8 Some compounds are missing from my HITLIST.

The hitlist is filtered according to a score cutoff defined in the PROJECTNAME.TAB file. Therefore poor scoring compounds are not reported in the HITLIST - this can be changed by opening the .tab file in a suitable text editor e.g. notepad in windows or vi and changing the DOCK1.r_ScoreThreshold value (by default it is -32). The scores for all compounds in a VLS screen are available in the PROJECTNAME.OU file.

You can also change this value in Graphical User Interface:

• Docking/Preference/Database Scan
• Change the Score Threshold Value

21.5.9 What constitutes a good docking score?

Generally a score below -32 is regarded as a good docking score. A good score depends on the system into which you are docking. For example is the pocket open or closed and are there metal ions interacting with the ligand. If the pocket is open scores higher than -32 may indicate potential binders. If a crystal structure is available remove the ligand and re-dock it to get an indication of approximately what is a good score for the receptor you are interested in.

21.5.10 When I view my docking run my ligand never jumps into the box - what did I do wrong?

Here are some reasons and some solutions for why your ligand is sampling outside of the binding pocket:

1. On Receptor Setup when it asks to move the initial probe - did you accidently move the probe outside the box?
2. Double check exactly where you built the maps (read one map in) in command line type read map "DOCK1_gl" ds map or check Docking/Review Adjust Ligand binding box
3. On the Docking/Interactive Docking/ LoadedLigand - did you check the box Use Current Ligand position? If so remove this option.

21.5.11 How do I identify the binding pockets in my receptor?

To do this go to:

• Tools/3D Predict/ICMPocketFinder

More information can be found in the section entitled Identifying Binding Pockets

21.5.12 How long does it take to dock one ligand using ICM-VLS?

It takes approximately 30-60 seconds per ligand depending on the size of the ligand and the nature of the pocket. ICM ranked first place compared to other leading docking software in terms of accuracy in a recent analysis undertaken by Astra Zeneca scientists.

See: On Evaluating Molecular-Docking Methods for Pose Prediction and Enrichment Factors Hongming Chen, Paul D. Lyne, Fabrizio Giordanetto, Timothy Lovell, and Jin Li J. Chem. Inf. Model.; 2006; 46(1) pp 401 - 415

21.5.13 What does thoroughness mean?

When you send a docking job either using Docking/Interactive or Docking/Run Docking Batch you are asked to enter a thoroughness value. This value represents the length of the docking simulation. The default value is 1. and this works well with nearly every kind of docking scenario, however in certain circumstances such as if you have a very large pocket this value should be increased slightly to a range of between 5. and 10.

21.5.14 When I setup the receptor I am asked to move a probe - what is this?

The probe which you see after Receptor Setup (Docking/ Receptor Setup) represents the initial starting position for the ligand. Usually this does not have to be changed as ICM by default places it into the center of the pocket. However if you do wish to move it to position closer to a critical region of the pocket you can do this using the middle mouse button when prompted in receptor setup.

21.5.15 I want to dock to the receptor and include other molecules in the receptor such as a tightly bound water molecule - how can I do this?

All molecules that you wish to dock to need to be stated in the Docking/Receptor Setup/ Receptor molecule (s) data entry box using the ICM selection language. For example if you wish to dock to the protein with PDB code 1m17 and water molecule number 20 you need to enter the information as shown below:

21.5.16 How can I run docking with a flexible receptor?

• First dock the ligand in the standard way (flexible ligand, rigid receptor).
• Then use Docking/Flexible Receptor /Refinement. This will allow the ligand and the receptor to be flexible during docking.

21.5.17 How can I run the docking simulation from the UNIX command line?

• Set your docking project up (eg, Set Project, Receptor Setup, Ligand Setup, Maps}

In the unix command line type:

/icm/rundock "DOCK1"

Where DOCK1 is the name of your docking project.

A variety of flags can be used with rundock:

 echo $prog": usage:   " $prog " <options> <project name> "
    -f <db entry from>"
    -t <db entry to>"
    -l <thoroughness> # change the length of MC docking, default is 1."
    -L <ligand list>  # dock selected compounds from the database"
    -i <ligand sdf>   # dock compounds from an SDF supplied"
    -n <scanName>     # change the run name in the output files"
    -a                # force docking and saving of all compounds"
    -s                # save stack conformations"
    -S                # evaluate score for all stack conformations (slow)"
    -d                # dock only (no scoring)"
    -j <nprocess>     # dock several ligands in parallel"
    -o                # redirect output to <project name>_from-to.ou"
    -c <output file>  # continue interrupted job with <output file>"
    -r                # dock rigid (no ligand flexibility)"
    -R <rand. seed>   # set random seed"
    -h                # show brief help"

21.5.18 I have a complex I wish to generate an ICM VLS Score for, however I did not dock it using VLS. How can I do this?

type in the command line:

scanScoreExternal

OR

• Docking/Tools/Evaluate ICM Score...

21.5.19 Why is there always a small difference between the score calculated interactively by scanScoreExternal and that obtained by docking (VLS)?

The reason for this is that ICM score has terms that require calculations on the reference 'free' state of the ligand, in particular solvation electrostatics and internal force-field strain energy change are calculated as a difference between free and bound state. VLS uses as a free state the lowest energy conformation found by MC search for the unbound ligand. Interactive score just minimizes the ligand locally. To ensure consistency we recomend you use one method or the other for scoring or you could recalculate the interactive score for your ligand from VLS before modifying/minimizing.

21.5.20 How do I monitor and terminate a background docking job?

If a background job is running you will see a message saying "1 bgrnd job" at the top of the gui interface (gui blue title panel).

To monitor the progress of the job:

1. Windows/Background Jobs
2. A panel will be displayed with information such as running time and percentage completed.

To terminate a background job:

1. Windows/Background Jobs
2. Right click on the job ID number and select "Terminate".

To view the current output of a background job:

1. Windows/Background Jobs
2. Right click on the job ID number and select "View Output"

When a background job has finished a message will appear in the graphical user interface

21.5.21 How do I sample flexible ring conformations (boat, chair etc..) during docking?

MolSoft's ICM docking algorithm has flexible ring sampling included on the fly. Just set ring sampling level to 1 (flex ring only in pre-sampling step) or 2 (throughout the simulation).

To do this:

• Set up the docking project (http://www.molsoft.com/gui/start- dock.html#docking-start)
• Before running the docking simulation go to Docking/Preferences/ General and change the flexible ring sampling level to 1 or 2.
• Now run the docking simulation (http://www.molsoft.com/gui/start- dock.html#begin-docking-simulation)

OR,

If you want to generate the conformations before docking and you have ICM-Pro + ICM-Chemistry then you can use the conformation generator algorithm described here: http://www.molsoft.com/gui/conf-gen.html

21.5.22 I am docking a racemic compound how can I sample both R andS states during docking?

To sample both R and S states of a compound during docking. Edit the project_name.tab file and edit l_sampleRacemin to yes

If l_sampleRacemic is 'yes', R and S states are sampled for racemic centers and best-fitting one is chosen. If it is 'no', they are kept fixed (in an aribtrary R or S state). Note that stereo centers that centers with pre-assigned R or S state are never sampled, if sampling is desired they need to be reassigned as racemic.