MovableType Tutorials

The MovableType or MT Method is a fast, free energy method based on recent work by Drs. Zheng Zheng and Kenneth M. Merz Jr. at Michigan State University. This patent pending method was licensed from MSU specifically to address the needs of the pharmaceutical industry (please see the literature for more information). The product is broken down into several key modules for small molecule conformational search (MTConfSearch), ligand docking (MTDock), protein:ligand affinity prediction (MTScore), and finally protein loop modeling (MTFlex).

The current modules available include two varieties of MTScore along with MTConfSearch. The other modules will be added throughout the year as they come on line, so please keep an eye on this website and Contact Us if you would like to consider the use of the technology in your own site. The tutorials currently available include:



Shell Environment

The shell (bash, tcsh, etc) environment is currently used to communicate certain settings to the MovableType (MT) modules within the DivCon Discovery Suite. These options will be folded into the software in the not too distant future as executable options, but currently the following environment variables should be set prior to running the MT calculations:

export MOL2_1SUBSTRUCTURE=1     # joins a single molecule ligand which may have been broken up into separate pieces



Structure Preparation

Structure preparation for MT-based methods isn't all that different from preparation for QM-based methods. You are free to use various 3rd party graphical user interface (GUI) platform such as MOE, Maestro, Sybyl, and so on. If you have any trouble, Contact Us for help and recommendations. Generally, the method can deal with both "united atom" and "all atom" approaches.

Additional Examples



Command Line: MTConfSearch

The MTConfSearch algorithm uses the same data developed for the MTScore algorithm in order to determine the most likely conformers of a ligand. This algorithm is often used as part of the MTScore tool (for sampling) but it can also be used independently. The method can take either a mol2 file or a SMILES string and generate the associated set of conformers (as an SDF).

In this example, the SMILES string is provided and all 30 unique conformers are written to the SDF using the -p (for publish) command line argument. 

% /path/to/DivConDiscoverySuite/bin/qmechanic c1ccccc1CCCC --mtcs -p sdf

Command line:
qmechanic c1ccccc1CCCC --mtcs
Version: DivCon Discovery Suite


Running on HOSTNAME
Processors: 1
# CONFORMER AFTER FIRST RUN: 36
TIME AFTER CONFORMER GENERATION: 0.003246 depth: 3

 

In addition to the SMILES approach, you can also provide a mol2 file with the associated ligand. Whether the input is SMILES or mol2, it should work the same and provide similar output.

% /path/to/DivConDiscoverySuite/bin/qmechanic butylbenzene.mol2 --mtcs -p sdf

Command line:
qmechanic butylbenzene.mol2 --mtcs 
Version: DivCon Discovery Suite 


Running on HOSTNAME
Processors: 1
# CONFORMER AFTER FIRST RUN: 36
TIME AFTER CONFORMER GENERATION: 0.003246 depth: 3

 

Additional Examples



Command Line: MTScore (Endstate)

The MTScore (EndState) or MTScoreES method is a fast free energy method which determines the end state binding affinity of a single conformer of a protein:ligand complex. Unlike with the ensemble score (or MTScoreE) the MTScoreES method only scores the final configuration and pose as provided, and gives one a quick understanding of whether that pose is representative.

As with MTConfSearch, MTScoreES is a fast and easy calculation to perform and it is highly scriptable in the command line. Currently, you must separate the protein from the ligand and provide these two items in two, separate files, but this will change in the not too distant future to allow you to "select" the ligand within a PDB. Correct protonation is suggested in order to aid in the automatic atom typing process.

% /path/to/DivConDiscoverySuite/bin/qmechanic 4w7t_protein.pdb 4w7t_ligand.mol2 --mtscore endstate

Command line:
qmechanic 4w7t_protein.pdb 4w7t_ligand.mol2 --mtscore endstate
Version: DivCon Discovery Suite 1 DivConDiscoverySuite-7.5.0-b4411


Running on HOSTNAME
Processors: 1
----------------------------------- MTScore ------------------------------------
"Species" "Interact" "E_Sol(complex)" "E_Sol(ligand)" "E_Sol(protein)"
--------------------------------------------------------------------------------
"4w7t_ligand" -232.787273 -6.310488 -8.545937 -13.371086
--------------------------------------------------------------------------------


----------------------------------- MTScore ------------------------------------
"Species" "MTScoreES"
--------------------------------------------------------------------------------
"4w7t_ligand" -9.066661
--------------------------------------------------------------------------------



Job Complete
Total Computation Time (Seconds): 6.29878
Fri Apr 27 16:33:59 2018

 

In this output, the MTScoreES (endstate) is written out in the final table. The previous table has various additional terms (including the gas phase interaction energy or "Interact."

 

Additional Examples



MOE GUI - MTScore (Endstate)

The MTScore (EndState) or MTScoreES method is a fast free energy method which determines the end state binding free energy of a single conformer of a protein:ligand complex. Unlike with the ensemble score (or MTScoreE) the MTScoreES method only scores the final configuration and pose as provided, and gives one a quick understanding of whether that pose is representative.

The MOE interface to MTScoreES is available through the use of the new qbWebServcice module. The following command is called prior to running MOE, and the 8080 port is provided as an argument in order for the webservice to "listen" on the 8080 port:

    $ /path/to/DivConSuite/bin/qbwebservice 8080

Note: this port on the "localhost" is currently hard coded in the MOE SVL script. If you prefer to have your webservice run on an alternate host (or alternate port), you may do so however you will need to edit line 8 of the $QBHOME/svl/qbWebService.svl file until a Preferences Panel has been provided.

After the qbWebService is running, you may start MOE and read in a protein and a ligand as per the CCG documentation. You may wish to familiarize yourself with the MOE documentation for the use of the Dock Panel. This documentation is available in your MOE installation at the following URL:

    file:///$MOE/html/apps/docking.htm#Using_the_Dock_Panel

When you run the MOE and the above noted CCG-provided tutorial, if you have properly installed the QuantumBio plugins to MOE, you should see an option such as the one circled in red below. You may choose this option during the tutorial to observe the execution in action. The resulting MTScore will be provided as the "S" Score in the dock.mdb file and the MTScoreES [QuantumBio] option can be chosen anywhere scores are used in MOE. 

 

Additional Examples



MTScoreE (Ensemble) with an External Docker

The MTScoreE (Ensemble) version of MTScore requires an ensemble of ligand poses to be generated and scored in order to sample the active site and accurately calculate a binding affinity. Generally, the better the poses the more accurate the affinity prediction, but the method can be quite forgiving.

Since each docking package (e.g. MOE, GLIDE, etcetera) is different and each has its own strengths and weaknesses, MTScore can be used to score an ensemble of poses provided by an external docking program as well as its own built in Heatmap docking approach (MTDock). In this example, we demonstrate the use the docking algorithm found within MOE. The concept though would be the same regardless of package (as long as the package can use and preserve the conformers provided by MTCS (Conformational Search). The following steps are performed:

The input/output associated with this calculation is available in the Bace_030215_CAT_4p.tar.gz file.

  1. (Temporary) Set several environment variables which are used to manipulate the calculation. These options will be moved to command line arguments a future release:

    % export MOL2_1SUBSTRUCTURE=1   # joins a ligand which may have been broken up into disparate pieces into a single ligand
    % export MT_SAMPLING_RANGE=0.2   # length of the MT blur vector
    % export DIVCON_INSTALL=/path/to/DiscoverSuite


  2. Create an empty directory and copy the input files (pdb and mol2) into the directory.

    % mkdir BACE ; cd BACE ; cp ../Bace_030215_CAT_4p.tar.gz . ; tar zxvf Bace_030215_CAT_4p.tar.gz
    % cp Bace_030215_CAT_4p/Bace_030215.pdb .
    % cp Bace_030215_CAT_4p/Bace_030215_CAT_4p.mol2 .


  3. Use MTConfSearch (--mtcs) to generate a set of conformers based upon the ligand provided. Note that both the target and the ligand are taken as input. This convention is in order to correctly generate the target.h5 file which will be automaticailly read by qmechanic in step 5. In addition to the target.h5 file, the ligand_conf.sdf file - including the generated MTCS conformers - is also produced using the --mtcs command line argument followed by the -p arguement (for publish).

    % ${DIVCON_INSTALL}/bin/qmechanic Bace_030215.pdb Bace_030215_CAT_4p.mol2 --mtcs -p sdf --np 4 -v 2


  4. Use MOEbatch to run a docking calculation with the resulting conformer SDF file using the SVL script provided with the DivConSuite. In this case, the receptor pdb file is provided using the -rec argument, the -lig argument is the ligand to be docked, and the -conf argument is the above noted ligand_conf.sdf file.

    % moebatch -licwait -run "${DIVCON_INSTALL}/svl/run/qbDockPair.svl" -rec Bace_030215.pdb -lig Bace_030215_CAT_4p.mol2 -conf Bace_030215_CAT_4p_conf.sdf -delwat


  5. Finally, run MTScore on the ensemble in order to calculation the ensemble score. In this example, the --mtscore input is the MOE-generated dock file while the other two input files are the same target.pdb and ligand.mol2 files used above.

    % ${DIVCON_INSTALL}/bin/qmechanic Bace_030215.pdb Bace_030215_CAT_4p.mol2 --mtscore Bace_030215_CAT_4p_dock.sdf --np 4 -v 2


    Command line:
    qmechanic Bace_030215.pdb Bace_030215_CAT_4p.mol2 --mtscore Bace_030215_CAT_4p_
    dock.sdf --np 4 -v 2 
    ....
    ---------------------------------- Pose Score ----------------------------------
    "Pose" "BF Intensity" "RMSD " "eSolv" "GARF Energy" "MTScoreES"
    --------------------------------------------------------------------------------
    0         -1.522      4.986    -11.808      0.000     -8.188
    1         -1.522      1.431    -10.474      0.000     -7.992
    3         -1.522      7.708    -21.721      0.000     -7.719
    2         -1.522      8.660    -14.916      0.000     -7.438
    4         -1.522      7.662    -16.837      0.000     -7.219
    --------------------------------------------------------------------------------

    -------------------------------- Final MTScore ---------------------------------
    "Species" "MTScoreES" "Binding ensembleZ" "Bound state" "Free state" "MTScoreE"
    --------------------------------------------------------------------------------
    "Bace_030215_CAT_4p"    -9.157335    -8.934408    -8.764213    -0.000003    -8.764210
    --------------------------------------------------------------------------------

    Job Complete 
    Total Computation Time (Seconds): 49.08843

The output is provided in tabular form with the following breakdown of information:

  • BFIntensiy = a value provided by MTCS which corresponds to the probability of the conformer.
  • RMSD = 3D structural root mean square deviation of the docked pose vs. the input mol2 pose.
  • MTScoreES = when in the Final MTScore table MTScoreES is the EndState binding affinity of the input mol2 file.
  • MTScoreE = when in the Final MTScore table, the MTScoreE is the Ensemble binding affinity of the ligand provided.

Additional Examples



MTScoreE (Ensemble) with MTDock

Please Note: MTDock is still undergoing significant refinement, optimization, and improvement. Until this initial effort is complete, it is recommended that you also run an external docker as noted in the previous tutorial.

As noted in the previous tutorial, the MTScoreE (Ensemble) version of MTScore requires an ensemble of ligand poses to be generated and scored in order to sample the active site and accurately calculate a binding affinity. Generally, the better the poses the more accurate the affinity prediction, but the method can be quite forgiving. You can of course use your own docking package (e.g. MOE, GLIDE, etcetera) as each is different and each has its own strengths and weaknesses. However, MTScore can be used to score an ensemble of poses provided by its own built in Heatmap docking approach (MTDock). In this example, we demonstrate the use the MTDock algorithm found within qmechanic. In contrast to the use of an external docker, qmechanic can be run alone in the following manner:

The input/output associated with this calculation is available in the Bace_030215_CAT_4p.tar.gz file.

     % ${DIVCON_INSTALL}/bin/qmechanic Bace_030215.pdb Bace_030215_CAT_4p.mol2 --mtscore --np 4 -v 2

 

Command line: qmechanic Bace_030215.pdb Bace_030215_CAT_4p.mol2 --mtscore -v 2 --np 4 

EstimatedNumberOfConformers: 7776
1stLoop Scoring TIME: 0.00132575
2ndLoop Scoring TIME: 0.00138322
3rdLoop Scoring TIME: 0.0013916
FINAL SCORING TIME: 0.0188621
 Complexing series: 
Pocket Atoms 
/A/SER/71//N
/A/SER/71//O
.....
Ligand Atoms 
/L//1//O1 6
/L//1//CL1 5
....
20 count 249578 58916 62 126.628 secs
ligandCentroid:  14.9468   -1.467 -1.10704. pocketCentroid: 13.7522 -0.3792 -0.6573
TIME COMPUTE LOOP Placement: 0.501662
TIME BIG OUTER LOOP Placement: 34.771574
TIME totalSetupTime Placement: 0.000000
TIME totalTimePart1 Placement: 34.772811
--------------------------------------------------------------------------------
RB Optimization
Cycle Total Energy (kCal)       Delta E    Grad. Norm     Grad. Max   Coord. Norm
--------------------------------------------------------------------------------
    0     1.99542790e+07    1.9954e+07    1.7231e+09    1.1265e+09    0.0000e+00
    1     5.06428214e+06   -1.4890e+07    3.0058e+08    2.8245e+08    0.0000e+00
....
Protonating...
Discovered hydrogen network in 8.7394e-02 secs.
Computed hydrogen network penalties in 1.1204e-05 secs.
Protonation Complete.
Total Best Energy: 0.0000e+00 in 4.5696e-05 secs.
Protonating...
Discovered hydrogen network in 8.5995e-02 secs.
Computed hydrogen network penalties in 7.5250e-06 secs.
Protonation Complete.
Total Best Energy: 3.0971e+00 in 3.6435e-05 secs.
....
---------------------------------- Pose Score ----------------------------------
"Pose" "BF Intensity" "RMSD " "eSolv" "GARF Energy" "MTScoreES"
--------------------------------------------------------------------------------
0         -1.305      0.512     -9.712    -56.578     -8.604
1         -1.305      1.513    -10.603    -54.951     -7.425
4         -1.305      4.609    -14.785    -51.469     -6.974
2         -1.305      4.766    -13.549    -52.962     -6.920
3         -1.305      4.252    -11.499    -52.548     -6.435
--------------------------------------------------------------------------------

-------------------------------- Final MTScore ---------------------------------
"Species" "MTScoreES" "Binding ensembleZ" "Bound state" "Free state" "MTScoreE"
--------------------------------------------------------------------------------
"Bace_030215_CAT_4p"    -9.157335    -9.074305    -8.751572     0.000005    -8.751577
--------------------------------------------------------------------------------

Job Complete 
Total Computation Time (Seconds): 233.38592

 

The output is provided in tabular form with the following breakdown of information:

  • BFIntensiy = a value provided by MTCS which corresponds to the probability of the conformer.
  • RMSD = 3D structural root mean square deviation of the docked pose vs. the input mol2 pose.
  • MTScoreES = when in the Final MTScore table MTScoreES is the EndState binding affinity of the input mol2 file.
  • MTScoreE = when in the Final MTScore table, the MTScoreE is the Ensemble binding affinity of the ligand provided.

 

Additional Examples