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Conformational Analysis for Small Molecules Using MacroModel and ConfGen 

Created with: Release 2018-1 

Prerequisites:  Release 2017-3 or higher Introduction to Structure Preparation and Visualization Mogul Configuration Setup 

Required Files: TorsionalScanning.prjzip, ConformationsPeptide.prjzip, KFGLE.txt, Ddrive 

Categories: Discovery Informatics, Structure Prediction and Analysis, Structure-Based Drug Design, Ligand-Based Drug Design 

Keywords: torsional scan, minimization, clustering, energy barrier, PLDB 

In this tutorial we will explore which tools are useful in exploring conformational space, from small                               molecules to protein-ligand complexes.  

Words found in the Glossary of Terms are shown like this: Workspace File names are shown with the extension like this: benzene.maegz Items that you click or type are shown like this: File > Import Structures 

This tutorial is written using a 3-button mouse with a scroll wheel and consists of the following                                 sections: 

1. MacroModel Prerequisites - p.1 

2. Creating Projects and Importing Structures - p.1 

3. Scanning Torsions and Understanding barriers - p.3 

4. Scanning Torsions for a Series of Molecules 

5. Generating Small Molecule Conformers 

6. Optimizing Conformations 

7. Clustering Methods 

8. Conclusion and References 

9. Glossary of Terms 

   

 

 

1. MacroModel Prerequisites Structure files obtained from the PDB, vendors, and other sources often lack necessary information                           for performing modeling-related tasks. Typically, these files are missing hydrogens, partial charges,                       side chains, and/or whole loop regions. In order to make these structures suitable for modeling                             tasks, we use the Protein Preparation Wizard to resolve issues. Similarly, ligand files can be sourced                               from numerous places, such as vendors or databases, often in the form of 1D or 2D structures with                                   unstandardized chemistry. LigPrep can convert ligand files to 3D structures, with the chemistry                         properly standardized and extrapolated, ready for use in virtual screening. In this tutorial, the proteins and ligands have already been prepared in order to save time. However,                                 these preparation steps are a necessary part of conformational analysis and must be done before                             using MacroModel. Please see the Introduction to Structure Preparation and Visualization tutorial for                         instructions on using the Protein Preparation Wizard and LigPrep. 

2. Creating Projects and Importing Structures At the start of the session, change the file path to your chosen Working Directory in Maestro to make                                     file navigation easier. Each session in Maestro begins with a default Scratch Project , which is not                               saved. A Maestro project stores all your data and has a .prj extension. A project may contain                                 numerous entries corresponding to imported structures, as well as the output of modeling-related                         tasks. Once a project is created, the project is automatically saved each time a change is made. 

Structures can be imported from the PDB directly, or from your Working Directory using File >                               Import Structures , and are added to the Entry List and Project Table. The Entry List is located to                                   the left of the Workspace . The Project Table can be accessed by Ctrl+T (Cmd+T) or Window >                                 Project Table if you would like to see an expanded view of your project data. 

 

1. Double click the Maestro icon to start Maestro 

○ (No icon? See Starting Maestro ) 2. In a browser, go to http://bit.ly/2xtMuOx 

to download the required tutorial files 

 Figure 2-1. Change Working Directory option. 

3. Navigate to File > Change Working Directory 

4. Navigate to your chosen directory and click Choose 

5. Copy the downloaded tutorial files to your Working Directory 

6. Unzip the tutorial file 

1 

 

 Figure 2-2. Open Project panel. 

7. Navigate to File > Open Project 8. Select the file, Torsional 

Scanning.prjzip  9. Click Open 

○ Structures are shown in the Entry List 

○ A structure is included in the Workspace 

 Figure 2-3. Warning box to save scratch project. 

10. In the Save scratch project warning box, click OK  

 Figure 2-4. Save Project panel. 

11.Click File > Save Project As  12.Change the File name to 

MM_Confgen_tutorial 13.Click Save 

○ The project is named MM_Confgen_tutorial.prj 

 Note: Please see the Glossary of Terms for the distinction between included and selected. 

   

2 

 

3. Scanning Torsions and Understanding Barriers In this sections, we will use MacroModel Coordinate Scan to setup and analyze simple torsions of a                                 single compound to gain a better understanding of the energetic barriers of a small molecule. We                               will superimpose the output conformations to a common core, for easier visualization. Next, we will                             use the potential energy surface to find low energy conformations of a small molecule. The potential                               energy surface of a compound can help with understanding key aspects of a molecule's behavior.                             This gives us an indication of how adaptable the molecule is and how much strain is needed for it to                                       adopt a particular conformation. These steps are a prelude to a full conformational search, which                             can explore many torsions of a small molecule simultaneously or systematically. We will use the                             potential energy surface to find low energy conformations of a small molecule. 

3.1 Set up a torsional scan 

 Figure 3-1. Select all entries in Ddrive and include the first entry. 

1. In the Entry List, select and expand the group Ddrive 

○ All entries are selected 2. Include the Ddrive_starting structure 

○ The structure, labeled by atom numbers, is in the Workspace 

 Note: You can apply atom number labels in the Style toolbox by clicking the Apply Labels dropdown and choosing Element + Atom Number 

 Figure 3-2. Coordinate Scan in MacroModel. 

3. Navigate to Tasks > Browse > MacroModel > Coordinate Scan 

○ The Coordinate Scan panel opens 

3 

 

 Figure 3-3. Choose Dihedral as Coordinate Type. 

4. Next to Use structures from, choose Workspace (included entry) 

5. Click the Scan tab 6. Next to Coordinate Type, choose 

Dihedral 

 Figure 3-4. Select dihedrals in the Workspace. 

7. In the Workspace , select atom numbers 1 , 14 , 15 , and 16 

○ Atoms are highlighted ○ Torsion 1 is defined  

8. Select atom numbers 1 , 6 , 25 , and 26 ○ Torsion 2 is defined 

4 

 

 Figure 3-5. Set solvent to ‘none’ for gas phase. 

9. In the Coordinate Scan panel, click the Potential tab 

10.Under Solvent, choose None ○ A gas phase minimization will be 

run 11.Next to Job name, type mmod_Ddrive 12.Click Run 

○ This job takes ~2 minutes to complete on 1 CPU 

○ To save time, we will look at pre-generated results 

3.2 Analyze torsional scan results 

 Figure 3-6. Include the lowest energy structure found and display properties in the Entry List. 

1. In the Entry List, click the cog  2. Choose Show Property 

 Figure 3-7. Show the Potential Energy property. 

3. Next to Subset, choose MacroModel All 4. Click Potential Energy-OPLS3 kcal/mol 5. Click OK 

○ The Potential Energy property is shown in the Entry List 

○ Widen the Entry List, if needed  Note: The Potential Energy-OPLS3 property is given in kJ/mol 

5 

 

 Figure 3-8. Potential and Relative Energy properties, shown in kcal/mol. 

6. Repeat steps 14 and 15, choose Relative Energy-OPLS3 kcal/mol 

7. Click OK 8. Type the A 

○ The Relative Energy property is shown in the Entry List 

 Note: The last entry in the Ddrive group is the lowest energy structure found from scanning the two dihedrals 

 Figure 3-9. Superposition option in Structure Alignment. 

9. Type A ○ Cursor is in Atom pick mode 

10.Navigate to Tasks > Browse > Structure Alignment > Superimposition 

○ The Superposition panel opens 

 Figure 3-10. Superpose by selected entries. 

11.Under Entries to superimpose, choose Selected Entries 

12.Click the SMARTS tab 

6 

 

 Figure 3-11. Select the pyrimidine core. 

13. In the Workspace , use shift-click to select the pyrimidine core 

14. In the Superposition panel, click Get from selection 

○ The selected structures are aligned to the pyrimidine core 

○ RSMDs for the structures are shown in the bottom of the panel 

 Figure 3-12. Fix the starting structure and toggle through the results. 

15. In the Entry List, double-click the In circle next to Ddrive_starting structure 

○ The structure is fixed in the Workspace 

16. Include the second entry 17.Use the left and right arrow keys to 

toggle through the conformations 

 Figure 3-13. Include multiple entries in the Workspace. 

Note: Use shift-click to include contiguous entries or ctrl-click (cmd-click) in include non-contiguous entries in the Workspace 

7 

 

3.3 View the potential energy surface 

 Figure 3-14. Plot Two Coordinate Scan option in MacroModel. 

1. Navigate to Tasks > Browse > MacroModel > Plot Two Coordinate Scan 

○ The Plot of Two-Coordinate Scan panel opens 

 Figure 3-15. Open the coordinate scan output. 

2. At the bottom left of the panel, click Open 

3. Double-click Ddrive and choose Ddrive-out.grd  

4. Click Open ○ The potential energy landscape is 

shown, colored rainbow ○ Low energies are shown in blue, 

high energies are shown in red 

 Figure 3-16. The Plot of Two-Coordinate Scan panel using kcal/mol energy units. 

5. Under Energy units, choose kcal/mol 6. Ensure that the Energy scale is set to 

Absolute ○ Min Energy 12.5 Kcal/mol (shown 

by blue green contour lines) ○ Max energy 34.9 Kcal/mol (shown 

by yellow red contour lines)  Note: The energy scale is absolute because we are only studying a single molecule, rather than comparing several molecules 

8 

 

 Figure 3-17. Analysis of the potential energy plot of the Ddrive molecule. 

Note: This plot shows there are large patches of lower energy with relatively sparse contour spacing between them. This suggests a reasonable freedom of movement of the two torsions relative to each other. However, when Torsion 2 lies close to 360/0°, no angle of Torsion 1 is tolerated well. By observing the energetic components, we can see this is due to the high VdW energy between the phenyl group and the nearby CH 2 group of Torsion 1. It causes the pyrimidine core to distort and result in a high energy bend. 

 Figure 3-18. Apply CPK representation to the starting and lowest energy structures. 

7. In the Entry List, double-click the In circle next to Ddrive_starting structure 

8. Ctrl-click (Cmd-click) to include the last two entries in the group 

○ The structure is un-fixed in the  9. Ctrl-click (Cmd-click) to include the last 

two entries in the group 10.Click Style and choose Apply CPK 

representation 

 

 Figure 3-19. Tiled view of a low and high energy conformation, showing a steric clash. 

11.Type ctrl-L (cmd-L) a. The Workspace is tiled b. The steric clash between the CH 2 

group and phenyl ring can be visualized 

12.Type ctrl-L (cmd-L) a. The Workspace is un-tiled 

13.Right-click empty Workspace and choose Clear Workspace 

9 

 

 Figure 3-20. Toggle properties on and off with the Property Tree.  

14.Type ctrl-T (cmd-T) a. The Project Table opens 

15.Click Tree to open the Property Tree  ○ Different calculated properties can 

be toggled on and off ○ Click the arrow next to each 

application to view more properties 

16.Double-click All a. All the properties are toggled off 

17.Dropdown MacroModel and Secondary 18.Under Secondary, check Bend Energy - 

OPLS3 kcal/mol and Van der Waal Energy - OPLS3 kcal/mol 

a. The Project Table is updated with the chosen properties 

 

4.  Scanning Torsions for a Series of Molecules  As part of a medicinal chemistry exploration project, it is often helpful to change a single-atom linker                                 in a molecule to evaluate the impact it has. We will use the change the linker atom in a series of                                         molecules and analyze the torsions to control the shapes of molecules of interest. Additionally, we                             will use the Protein-Ligand Database (PLDB) to examine the statistics of these type of torsions in                               similar molecules over the PDB. Good agreement between the statistics of known structures and the                             torsion scan results can be used benchmark calculation setup. For more information on using the                             PLDB, please see the Protein-Ligand Database Tutorial . Please note that you will need to purchase a                               license for the PLDB to follow this section of the tutorial. 

4.1 Set up the scans 

 Figure 4-1. Include the first entry of the Phenyl-linker-Pyridyl group. 

1. In the Entry List, expand and select the group Phenyl-linker-Pyridyl 

2. Include the first entry, Ph-O-Py 3. Navigate to Tasks > Browse > 

MacroModel > Coordinate Scan ○ The Coordinate Scan panel opens 

 

10 

 

 Figure 4-2. Set the two dihedral angles. 

4. Next to Use structures from, choose Workspace (included entry) 

5. Click the Scan tab 6. Next to Coordinate Type, choose 

Dihedral 7. In the Workspace , select atom numbers 

3 , 2 , 12 , and 15 ○ Atoms are highlighted ○ Torsion 1 is defined  

8. In the Workspace , select atom numbers 14 , 15 , 12 , and 2 

○ Torsion 2 is defined 

 Figure 4-3. Set solvent to ‘none’ for gas phase. 

9. In the Coordinate Scan panel, click the Potential tab 

10.Under Solvent, choose None ○ A gas phase minimization will be 

run 11.Next to Job name, type drive_PhOpy 12.Click Run 

○ This job takes ~10 minutes to complete on 1 CPU 

○ To save time, we will look at pre-generated results 

11 

 

 Figure 4-4. Repeat the coordinate scan setup for the series of molecules. 

13. In the Entry List, include Ph-S-Py ○ The linker is now a sulfur atom ○ C-S has a greater bond length 

14.Repeat steps 5-12, naming the job drive_PhSpy 

15.Repeat steps 13-14 for Ph-CH2-Py and Ph-NH2-Py , changing job names 

○ This jobs takes ~10 minutes each to complete on 1 CPU 

○ To save time, we will look at pre-generated results 

 Note: Ensure that atoms are chosen in the same order across all calculations. Reversing the order will make interpreting the results nonsensical. Keep torsion 1 and torsion 2 equivalent across the series. 

4.2 Analyze the results of the linker series 

 Figure 4-5. Filter the Entry List. 

1. In the Entry List, click the Search magnifying glass  

2. Type Minimum 3. Click the arrow next to each filtered 

group to expand ○ Only the entry with the minimum 

energy is shown 4. Shift-click to include all four minimum 

energy entries 

12 

 

 Figure 4-6. Tile view of the four energy minimized conformations. 

5. Type ctrl-L (cmd-L) ○ The Workspace is tiled 

6. Type ctrl-Y (cmd-Y) ○ The Preset rendering is applied 

 Figure 4-7. Superimpose included entries by SMARTS. 

7. Navigate to Tasks > Browse > Structure Alignment > Superimposition  

○ The Superposition panel opens 8. Next to Entries to superimpose, choose 

Included entries 9. Click the SMARTS tab 10. In the Workspace , use shift-click to 

select a pyridine 11. In the Superposition panel, click Get 

from Selection 12.Type ctrl-L (cmd-L) 

○ The Workspace is un-tiled 

13 

 

 Figure 4-8. The lowest energy conformations of the linker series compounds. 

Note: As seen in Figure 4-8, changing the linker from an oxygen (white) to a sulfur (green), the phenyl ring changes orientation with respect to the pyridyl nitrogen. The CH 2 linker induces the least planar conformation, due to sterics, while the NH 2 linker is most coplanar with the pyridyl ring. 

4.3 Examine predicted torsions against PLDB data (optional) 

 Figure 4-9. Clear the Entry List filter. 

1. Click the X to clear the Entry List filter 2. Include 1XLS (unprepared) 3. Type L 

○ The Workspace is zoomed to the           ligand 

 Figure 4-10. The bound ligand agrees with predicted lowest energy O-linked conformation. 

Note: The orientation of the bound ligand around the O-linker agrees with the lowest energy conformational result for the O-linked compound in section 4.2. 

14 

 

 Figure 4-11. The bound ligand conformation is influenced by the CF 3 group. 

4. Include 2WAP (unprepared) 5. Type L 

○ The Workspace is zoomed to the ligand 

 Note: The orientation of the bound ligand around the O-linker is ~180° different to the lowest energy conformational result for the O-linked compound in section 4.2. The strongly electron-withdrawing CF 3 group on the bound ligand has weakened the conformational preference of the lone pair electrons on the oxygen linker. 

 Figure 4-12. PLDB Search option in Structure Analysis. 

6. Navigate to Tasks > Browse > Structure Analysis > PLDB Search 

○ The Connect to PLDB Search panel opens 

7. Enter your Server URL, User Name, and Password 

8. Click Log In ○ The PLDB Search panel opens 

 Note: You must have a PLDB license to do these steps. 

 Figure 4-13. Open a new search in PLDB. 

9. Click New Search ○ The PLDB Search - Sketcher 

opens 

15 

 

 Figure 4-14. Draw the N-linked series compound. 

10. In the Sketcher, draw the PhNH2Py structure from section 4.1 

 Figure 4-15. Select the first torsion. 

11.Click Torsion 12.Click on each atom in the first NH 2 linker 

torsion to make the torsion measurement 

 Figure 4-16. Input torsion limits for the search. 

13. In the Input torsion limits panel, next to Is between, type 0 and 360 

14.Click Ok ○ The torsion search is highlighted in 

green 

16 

 

 Figure 4-17. Select the second torsion. 

15.Repeat steps 39-41 for the second NH2 linker torsion 

 Figure 4-18. Start PLDB search. 

16.Click Start Search ○ This search takes ~1 minute ○ Results are shown in the PLDB 

Search panel 

 Figure 4-19. View PLDB search results. 

17.Click View Results (61) 

17 

 

 Figure 4-20. Scatter plot of the search results. 

18.Click Show Plots/Hide Plots 19.Choose the Scatter Plot tab 

○ Two conformations are preferred in the literature 

○ The two low energy conformations are ~180° different 

20.Close the PLDB Search Results and PLDB Search panels 

 

5. Generating Small Molecule Conformers MacroModel is an engine for conformational searching, with substantial options for controlling                       solvents, forcefields, constraints, and settings associated with navigating a potential energy surface.                       In this section, we will explore how the choice of solvent affects the conformations that can be found                                   for a small peptide, KFGLE. This peptide has been designed to allow the possibility of a salt bridge                                   interaction between the sidechains of the two terminal lysine and glutamic acid. We will compare                             different searching methods, observing that some that allow this interaction to dominate, and others                           do not. This highlights how the solvent environment of a system is an important consideration for                               obtaining a meaningful set of conformers. 

5.1 Set up conformational searches 

 Figure 5-1. Open ConformationsPeptide project. 

1. Go to File > Open Project 2. Choose the file, 

ConformationsPeptide.prjzip 3. Click Open 

○ Structures are shown in the Entry List 

○ The KFGLE structure is included in the Workspace 

4. In the Save scratch project warning box, click OK  

18 

 

 Figure 5-2. Save project as MM_peptide. 

5. Go to File > Save Project As  6. Change the File name to MM_peptide 7. Click Save 

○ The project is named MM_peptide.prj 

○ Entry KFGLE is included 

 Figure 5-3. Conformational Search option in MacroModel. 

8. Go to Tasks > Browse > MacroModel > Conformational Search 

○ The Conformational Search panel opens 

 Figure 5-4. Potential tab in Conformational Search. 

9. In Use structures from, choose Workspace (included entries) 

10. In the Potential tab, next to Solvent, choose Water 

19 

 

 Figure 5-5. Mini tab in Conformational Search. 

11.Click the Mini tab 12.Next to Maximum iterations, type 2000 13.Next to Job name, type 

peptide_cs_2000it_water 14.Click Run 

○ This job will take 10-15 minutes to complete on 1 CPU 

○ To save time, we will look at pre-generated results 

15.Repeat steps 10-14, choosing CHCl3 as the solvent and naming the job peptide_cs_2000it_chcl3 

○ This job will take 10-15 minutes to complete on 1 CPU 

○ To save time, we will look at pre-generated results 

 Figure 5-6. Bioactive Search option in Structure Analysis. 

16.Go to Tasks > Browse > Structure Analysis > Bioactive Search 

○ The ConfGen panel opens 

20 

 

 Figure 5-7. ConfGen panel. 

17.Next to Use structures from, choose Workspace (1 included entry) 

18.Next to Target number of conformations, type 50 

19.Change the Job name to KFGLE_ConfGen 

20.Click Run ○ This job will take ~5 minutes to 

complete on 1 CPU ○ To save time, we will look at 

pre-generated results 

5.2 Analyze and compare the conformational search results 

 Figure 5-8. Include the results in the Workspace. 

1. In the Entry List, right-click the group peptide_cs_2000it_water-out 

2. Choose Include 3. In the Warning box, click Continue 

○ The structures are included in the Workspace 

4. Ctrl-click (Cmd-click) to un-include KFGLE 

 Figure 5-9. The Interactions panel. 

5. In the Workspace Configuration Toolbar, right-click Interactions 

6. Click the ... ○ Interactions panel opens 

7. Next to Non-covalent bonds, choose Intra-Ligand 

8. Under Contacts/Clashes, toggle off Bad and Ugly 

21 

 

 Figure 5-10. Intramolecular interactions of the peptide conformations generated in water. 

Note: The intramolecular hydrogen bonds and salt bridge of the conformations generated in water align well.  

9. In the Entry List, right-click peptide_cs_2000it_water-out 

10.Choose Exclude ○ The structures are removed from 

the Workspace 

 Figure 5-11. Intramolecular interactions of the peptide conformations generated in chloroform. 

11. In the Entry List, right-click on the group peptide_cs_2000it_chcl3-out 

12.Choose Include 13. In the Warning box, click Continue 

○ The structures are included in the Workspace 

 Note: The are more intramolecular interactions when the peptide is modeled in chloroform, as compared to water. 

22 

 

 Figure 5-12. The Property Table with only AromaticBond, Halogen, HBond and SaltBridge added.  

14.Type ctrl-T (cmd-T) ○ The Project Table opens 

15.Click the Property Tree icon ○ The Property Tree appears on the 

right of the Project Table 16.Click the All box twice 

○ All boxes are deselected 17.Next to Maestro, click the arrow 18.Check AromaticHBond, Halogen, 

HBond, and SaltBridge ○ These properties are shown in the 

Project Table  

23 

 

 Figure 5-13. The Calculate Properties panel. 

19.Select both the water and chloroform output groups 

20. In the Project Table, go to Data > Add Property > Standard Mol 

○ The Calculate Properties panel opens 

21.Select Number of h-bonds and halogen bonds and Number of Pi interactions by Ctrl + clicking   

22.Click on Selected Entries ○ This updates the Project Table 

with new columns containing the values for all selected rows 

 

24 

 

 Figure 5-14. View of the Entry List with the selected results and the first entry included. 

23.Right Click on the Workspace and select             Clear Workspace 

24.Click on the KFGLE_ConfGen group         header to select the whole group 

25. Include the first entry in the Workspace 

 

 Figure 5-15. Measuring a distance in one             conformation and applying it to all selected             entries.  

26. In the Favorites toolbar, choose Measure  27. In the banner that opens, set the             

measure field to Distance from the           dropdown 

Define the measurement of the terminal           residues, K and E 

28.Pick the two atoms in the Workspace  ○ This measures the distance for a           

single molecule 29.Right-click the distance label in the           

Workspace 30.Select Calculate Property… 

○ This opens the Calculate       Measurements Property window 

25 

 

 Figure 5-16. The Project Table showing the             newly added column (highlighted in red) for the               Distance property calculated for all         conformations. 

31.Define a new Property name or keep the               default; click OK 

○ This creates a new column in the             Project Table. By default, it is           named as Distance atom number -           atom number 

     

 

 Figure 5-17. Results of Entry ID vs Distance to show distribution of extended conformations coming from ConfGen (top) and non-extended conformations coming from MacroModel -water solvent model (bottom) . 

Note: Plots have been pre-generated for easy viewing 

32.Click the Plot icon in the Project Table ○ The Manage Plots panel opens         

and there are two scatter plots           that are already present and         named  

33.Click on each of the Plots to view them                 (figure 4-13) 

Note: You can also create new plots from               scratch in the Manage Plots panel 

34.Choose New scatter plot ○ An empty Scatter Plot opens as a             

new Window 35.Define the X axis as Entry ID and Y axis                   

as Distance to generate a new scatter             plot 

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5.3 Build a peptide (optional) 

 Figure 5-18. A view of the built peptide imported                 into Maestro. 

Create a text file with the one letter residue                 letters for the peptide you want to build.  

36. In this case type KFGLE 37.Save it is KFGLE.txt 

Open a Schrodinger Command Prompt window           and use the following commands to run the               script for building the peptide on your             respective OS Linux:   $SCHRODINGER/run build_peptide.py -cap KFGLE.txt peptide-out.mae Windows:   run build_peptide.py -cap KFGLE.txt peptide-out.mae 

38.Navigate to File > Import structures…           and select peptide-out.mae 

 Figure 5-19. The original build panel shown with               Fragments set to Amino acids. 

Alternatively, if you have previously used the             original (old) build panel it can still be accessed                 in new Maestro from the Command Window             Input Area 

39.Type showpanel build in the Command           Window Input Area 

○ The Build panel is now displayed           and here you can place and grow             fragments for amino acids, define         the grow direction, joining       geometry and secondary structure 

 

 

6.  Optimizing Conformations with Mogul Mogul is a program that can be used to validate molecular geometries, as it contains precise                               information on preferred molecular geometries through access to millions of chemically classified                       parameters derived from the CSD. It is setup to check on bond lengths, valence angles, acyclic                               torsion angles, and ring conformations, and such searches are directly accessible through Maestro                         

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GUI, under Tasks. This is, however, a license-based tool from CCDC and requires configuration to                             set up. Please refer to Configuring Mogul for Maestro Use for how to setup Mogul. 

 Figure 6-1. Finding CSD panels in Tasks 

1. In Tasks > type Mogul and click Enter  2. Click CSD Search 

○ This CSD panel opens 

 Figure 6-2. The Query CSD panel. 

3. Include the first entry from ConfGen group 

4. Under Query CSD with ligand from, select Workspace  

5. Under Search fragments, choose All torsions 

6. Click the Job Settings cog 

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 Figure 6-3. The Job settings panel to run CSD search on Host mogul-query (12 processors) 

7. Click the Settings Button (cog) ○ The Job Settings panel opens 

8. Under Host, select mogul-query(12) 9. Set Job Name to csd_search-peptide 10.Click Run 

○ This job should take ~1 minute to complete 

9. When the job finishes, click incorporate in the banner 

 Figure 6-4. The offensive torsion C77-C80 with a value of 12.31 is shown in red in the Workspace and in the Analysis Panel 

10. In Tasks > type Mogul and click Enter 11.Click CSD Analysis 

○ Each torsion is shown qualitatively (green = ok and red = bad), and is interactive with the Workspace  

○ Torsion C77-C80 is outside the range of where other torsion hits are found in the CSD. Ideally, it should lie between 40 and 80 degrees and 160-180 degrees 

 

11.Click on the torsion, C77-C80 ○ A histogram is displayed showing 

the distribution of the torsion hits found in the CSD  

Note: For more details on Mogul, please refer to the link here  

13.Go to File > Close Project  

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Figure 6-5. A histogram showing torsion C77-C80 (red line) to be outside the distributions of torsion hits found in the CSD (green bars). 

7. Clustering Methods In Maestro, we can Cluster by Conformations using torsions or atomic positions, which we will                             explore here.  

 Figure 7-1. Select all entries in Ddrive and include the first entry. 

1. Go to File > Open Project 2. Select Torsional Scanning.prjzip and 

click Open ○ Structures are shown in the Entry 

List 3. Select and expand the group Ddrive 

○ All entries are selected 4. Include the Ddrive_starting structure 

○ The structure, labeled by atom numbers, is in the Workspace 

 Figure 7-2. Using the Tasks search to find the Clustering of Conformers option. 

5. Go to Tasks > search for Cluster and click Enter 

6. Select Clustering of Conformers ○ The Conformer Cluster panel 

opens  

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 Figure 7-3. The Conformer Cluster panel. 

7. For Use structures from, choose Project Table (1371 selected entries) 

8. For Generate RMSD Matrix, choose Atomic RMSD 

9. For Define comparison atoms, choose Heavy atoms 

○ The heavy atoms are listed in the window above 

10.For Linkage method, choose Average 11.For Number of clusters to generate, type 

100  12.For Incorporation, choose One structure 

(nearest to centroid) per cluster  13.Change the Job name to 

conf_cluster_atom 13.Click on Run 

○ This job takes about 3-4 minutes to complete 

 Figure 7-4. The Clustering Statistics panel. 

14.Click Clustering Statistics  ○ The Clustering Statistics panel 

opens 15.Under Plot, choose the Kelley Penalty 

from the drop-down menu and observe the plot 

○ In this case around 53 clusters are ideal as the penalty is at its the lowest. This can be seen by hovering on the plot in that area which updates the x and y-variable value at the top-right hand side of the panel  

 Note: Clicking in the plot sets the number of clusters in the Conformer Cluster panel 

8. Conclusions and References MacroModel is a powerful tool to explore the full range of conformations for small molecules, and                               has can also be used to analyze protein-ligand complexes. We have examined how specific settings                             

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can make a difference to the conformational output, so understanding the choices you make are                             important to the results. Through the exploration of small molecules, we observed how                         conformations can vary due to a single atom change and how this information can be used in lead                                   optimization.  For further information, please see: Macromodel User Manual Protein-Ligand Database Tutorial  

9. Glossary of Terms Entry List - a simplified view of the Project Table that allows you to perform basic operations such as selection and inclusion 

included - the entry is represented in the Workspace, the circle in the In column is blue 

incorporated - once a job is finished, output files from the Working directory are added to the project and shown in the Entry List and Project Table 

Project Table - displays the contents of a project and is also an interface for performing operations on selected entries, viewing properties, and organizing structures and data 

Scratch Project - a temporary project in which work is not saved, closing a scratch project removes all current work and begins a new scratch project 

selected - (1) the atoms are chosen in the Workspace. These atoms are referred to as "the selection" or "the atom selection". Workspace operations are performed on the selected atoms. (2) The entry is chosen in the Entry List (and Project Table) and the row for the entry is highlighted. Project operations are performed on all selected entries  

Working Directory - the location that files are saved 

Workspace - the 3D display area in the center of the main window, where molecular structures are displayed 

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