1. Double-click the Materials Science icon
   • (No icon? See Starting Maestro)

Figure 2-1. Change Working Directory option.

2. Go to File > Change Working Directory
3. Find your directory, and click Choose
4. Pre-generated files are included for running jobs or examining output. Download the zip file here: schrodinger.com/sites/default/files/s3/release/current/Tutorials/zip/nitrosamine.zip
5. After downloading the zip file, unzip the contents in your Working Directorythe location where files are saved for ease of access throughout the tutorial

Figure 2-2. Save Project panel.

6. Go to File > Save Project As
7. Change the File name to nitrosamine_tutorial, click Save
   • The project is now named nitrosamine_tutorial.prj

Figure 2-3. Import structures.

For this example, the small molecule structures relevant to the reactions of interest are provided.

8. Go to File > Import Structures
9. Choose input_structures.maegz from the provided tutorial files
10. Click Open

Figure 2-4. Visualizing the imported structures.

The input structures for the reactants and products are added to the entry lista simplified view of the Project Table that allows you to perform basic operations such as selection and inclusion. Please proceed to visualize the five structures in the workspacethe 3D display area in the center of the main window, where molecular structures are displayed. For practicing drawing these molecules, see the Introduction to Materials Science Maestro tutorial.

Figure 3-1. Opening the AutoTS panel.

1. Go to Tasks > Materials > Quantum Mechanics > Molecular Quantum Mechanics > More Molecular QM Tasks > AutoTS
   • Alternatively, you can search for AutoTS in the search bar of the Tasks menu
   • The AutoTS panel opens

Figure 3-2. Importing reactants in the AutoTS panel.

2. Outside of the panel, select(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 the Reactants (2) group in the workspacethe 3D display area in the center of the main window, where molecular structures are displayed
3. In the Reactants section of the panel, choose From Project Table (2 selected entries) to Import
   • The reactants - dimethylamine and nitrous acid are loaded

Figure 3-3. Importing products in the AutoTS panel.

4. Outside of the panel, select(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 the Products (2) group in the workspacethe 3D display area in the center of the main window, where molecular structures are displayed
5. In the Products section of the panel, choose From Project Table (2 selected entries) to Import
   • The products - n-nitrosodimethylamine and water are loaded

Figure 3-4. Changing the Reaction Name and the Job name.

6. Change the Reaction Name to Reaction_NDMA and the Job name to jag_transition_search_NDMA

Figure 3-5. Generating reaction complexes.

7. Go to the Preview Reaction Complex tab
8. Click Generate Complexes
   • This will generate the pre-reactive (entrance) and post-reactive (exit) complexes. These complexes are used to generate a reaction path and transition state guess.
   • This job will take a few minutes.

Figure 3-6. Viewing the reactant and product complexes

The output will be two new entries to the entry lista simplified view of the Project Table that allows you to perform basic operations such as selection and inclusion. These are the reactant and product complex guesses. Feel free to visualize these structures in the workspacethe 3D display area in the center of the main window, where molecular structures are displayed.

Figure 3-7. Setting up and running the job.

9. Go to the Advanced Settings tab
   • This tab has settings for the reaction complexes, the reaction workflow, and for the individual Jaguar calculations performed in the workflow.
10. Check Compute Energies at Infinite Separation
    • When this option is selected, the free energy of the reaction is also computed. This option involves a frequency calculation on the isolated reactant and product molecules.
    • Adjust the job settings () as needed
    • This job requires a CPU host. The job can be completed in about 2 hours.
11. If you would like to run the job, click Run. Otherwise, pre-generated results are provided.
12. Close the AutoTS panel

Figure 3-8. Loading the output file.

If you would prefer to proceed with pre-generated results, you can import via File > Import Structures. Navigate to where you downloaded the tutorial files and choose the Section_03 > jag_transition_search_NDMA > jag_transition_search_NDMA_AutoTS > jag_transition_search_NDMA_full_path.mae file.

Figure 3-9. Viewing the reaction energetics.

13. When the job is finished or after importing, use the WAM (Workflow Action Menu) button() to open the View Energetics panel
    • The energy profile shows a transition state with an activation energy of ~21.2 kcal/mol.

Figure 3-10. Verifying the transition state structure.

We should verify the transition state by analyzing the frequency calculation

14. Open the Vibrations directly from the entry list by clicking on the button ( )
    • Notice that there is one negative frequency. A transition state should have exactly one negative frequency, and this vibrational mode should be associated with the bond breaking and/or forming process. See Locating Transition States: Part 1 and Part 2 tutorials for a detailed demonstration on transition states calculation.
15. Visualize this vibration by clicking on the play button
    • We can see that the vibration resembles the expected transition state, which is good evidence that this is the transition state of interest
16. Close the Vibrations pop up

Figure 4-1. Opening the Create Reaction Network Profiler Input panel.

1. Select(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 the output entry group from the AutoTS calculation
   • All three entries should be selected
2. Go to Tasks > Materials > Quantum Mechanics > Reaction Network > Create Reaction Network Profiler Input
   • The Create Reaction Network Profiler Input Structures panel opens
   • Alternatively, the panel can also be opened from the search bar in the Tasks menu

Figure 4-2. Importing the AutoTS reaction network.

3. Click Import Selected Entries for Automatically populate groups from existing reaction network entries
   • The panel is populated with reactant, transition state and product groups in the Groups of Conformers section

Figure 4-3. Preparing the reactant group.

4. Select(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 and includethe entry is represented in the Workspace, the circle in the In column is blue the reactant entry in the entry lista simplified view of the Project Table that allows you to perform basic operations such as selection and inclusion
5. For Indices of atoms to keep click Define
6. Enter at.n 2,7,11-14 for the ASL selection.
   • If you have run the AutoTS calculation and not imported the provided files, then select the atoms in the workspacethe 3D display area in the center of the main window, where molecular structures are displayed as shown in the figure and use it for the ASL selection using the Selection option
7. Click OK

Figure 4-4. Setting Indices of superposable atoms.

8. For Indices of atoms to superposable atoms check Pick Atoms
9. Click on C, N, and C atoms of the reactant in the workspacethe 3D display area in the center of the main window, where molecular structures are displayed in that order.
   • Note that the selection order of the superimposable atoms is critical, so it is recommended that you keep the same order of superposable atoms between all reaction network groups.
   • Atoms sequence 1,2,3 is updated in the panel

Figure 4-5. Create Reaction Network Input Structures for transition state structure.

10. Scroll down in the panel to group (2)
11. Ensure that Sibling group name is transition_state_1
12. Ensure reactant is added for Add parent group name
13. For Indices of atoms to keep enter 2,7,11,12,13,14
14. For Indices of superposable atoms enter 1,2,3
15. Ensure that the Indices of atoms to restrain and Atom index pairs of distances to restrain are automatically populated from the AutoTS output
16. Ensure Transition state is checked

Figure 4-6. Create Reaction Network Input Structures for product.

17. Scroll down in the panel to group (3)
18. Change Add parent group name to transition_state_1
19. Click Add
20. Repeat steps 13-14 from this section

Figure 4-7. Running the Create Reaction Network Input Structures job.

21. Change the Reaction network name to rxnwf_input_AutoTS
22. Check Ensure mass is conserved
23. Click Run
24. Close the panel

Figure 4-8. Output from the Create Reaction Network Input Structures job.

This job should finish almost instantly. A new rxnwf_input_AutoTS (3) group is 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 in the entry lista simplified view of the Project Table that allows you to perform basic operations such as selection and inclusion, and the first group entry, reactant, is includedthe entry is represented in the Workspace, the circle in the In column is blue in the workspacethe 3D display area in the center of the main window, where molecular structures are displayed. The structures match our inputs, but now have the necessary information for swapping fragments and running the reaction network profiler in the next steps.

Figure 4-9. Opening the Swap Fragments panel and importing the reference structures.

25. Keeping the previous entry 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, go to Tasks > Materials > Quantum Mechanics > Reaction Network > Swap Fragments
    • The Swap Fragments panel opens
26. In the Reference Structures section of the panel, next to Import reference structures from selected entries, click Import
    • All of the reference structure information is populated in the panel

Figure 4-10. Running the Swap Fragments job.

27. Select(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 and includethe entry is represented in the Workspace, the circle in the In column is blue the diethylamine entry in the entry list
28. In the Novel Structure section of the panel click Import from Workspace
29. For Specify a collection of atom indices to be replaced enter 3,11
    • These correspond to the N and H atoms of the amine.
30. For Specify novel atom indices for superposition enter 2,3,4
    • These indices are the atoms in the new reactant that align with our reference atom indices for superposition in the template structure.
31. Click Run
32. Close the Swap Fragments panel

Note: We can potentially create a large library of swapped reaction complexes using multiple inputs for Novel Structure. This will save time from creating individual complexes manually. In this example, we are only introducing the mechanics for one substitution.

Figure 4-11. Output of the job after renaming.

33. This job should finish almost instantly. A new rxnwf_input_AutoTS (3) group is 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 in the entry lista simplified view of the Project Table that allows you to perform basic operations such as selection and inclusion, and the first group entry, diethylamine_reactant, is includedthe entry is represented in the Workspace, the circle in the In column is blue in the workspacethe 3D display area in the center of the main window, where molecular structures are displayed.
34. Change the entry group name to rxnwf_input_diethyamine

Figure 4-12. Importing structures into the Reaction Network Profiler Calculations panel.

35. Go to Tasks > Materials > Quantum Mechanics > Reaction Network > Reaction Network Profiler Calculations
    • The Reaction Network Profiler panel opens
36. Click Import
    • (3 structures imported) indicates that the input has been loaded into the panel

Figure 4-13. Additional Jaguar settings.

37. Ensure that Conformational Search is checked
38. Click Jaguar Options
39. Change the Theory to B3LYP-D3
40. Change the Basis set to 6-31G**
41. Increase the Maximum interactions to 300
42. Change the Maximum steps to 150
43. Check Use special measures to prevent convergence failure
44. Click OK
    • The Jaguar section of the panel updates with the new functional and basis set.

Figure 4-14. Running the job.

45. Check Return Jaguar job files
46. Change the Job name to reaction_profiler_NDEA
47. Adjust the job settings () as needed
    • This job requires a CPU host. The job can be completed in about 1 hour.
48. If you would like to run the job, click Run. Otherwise, pre-generated results are provided.
49. Close the panel

Figure 4-15. Output of the Reaction Network Profiler job.

If you would prefer to proceed with pre-generated results, you can import via File > Import Structures. Navigate to where you downloaded the tutorial files and choose the Section_04 > reaction_profiler_NDEA > reaction_profiler_NDEA-out_rxnwf.mae file.

When the job finishes or after importing, a new entry group titled reaction_profiler_NDEA (14) is added to the entry list. Feel free to visualize any of the complexes in the workspace. You can view the vibration frequencies as we did in Section 3 and verify for all the transition state conformers.

Figure 4-16. Viewing the reaction profile.

The output files include a .pdf file, which contains the various useful energy diagrams. On your computer (outside of MS Maestro), open reaction_profiler_NDEA_e_diagrams.pdf in any PDF viewer and locate Total_Free_Energy_(kcal/mol)_298.15K_1.00E+00atm_stage_2. The energy profile represents the Boltzmann averaged Free Energy profile for the reaction.

Alternatively, you can also generate the reaction energy profile using the Reaction Profile Viewer. For a more detailed demonstration see Calculating Reaction Energetics for Molecular Systems or Locating Transition States: Part 1 tutorials.

You can also find more details about the reaction like the equilibrium constant for the transition state and turnover frequency (using the Energetic Span method) in the reaction_profiler_NDEA_custom_keq.csv and reaction_profiler_NDEA_tof.csv files respectively.

Figure 5-1. Importing the structure.

1. Go to File > Import Structures
2. Choose n-nitrosomethylamine.mae from the provided tutorial files
3. Click Open

Figure 5-2. Opening the Nanoreactor panel.

4. Select(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 and includethe entry is represented in the Workspace, the circle in the In column is blue the imported entry
5. Go to Tasks > Materials > Quantum Mechanics > Nanoreactor
   • The Nanoreactor panel opens

Figure 5-3. Running the Nanoreactor job.

6. Change the Relaxation time to 10 ps
   • This system is small so increasing the relaxation time of the molecular dynamics simulations will not increase the total time the calculation takes by an exorbitant amount.
7. Check Refine final energy
   • This setting introduces a DFT calculation on nanoreactor products, specifically electronic energy is calculated with DFT and thermal corrections are calculated with GFN2-xTB. Be aware that adding this parameter might significantly increase computation time, especially for large molecules.
   • We will use the default settings for the rest of the parameters.
8. Maintain Replicates as 8
   • The Replicates setting indicates the number of trajectories.
9. Change the Job name to nanoreactor_nitrosamine
10. Adjust the job settings () as needed
    • This job requires a CPU host. The job can be completed in about 2 hours.
11. If you would like to run the job, click Run. Otherwise, pre-generated results are provided.
12. Close the Nanoreactor panel

Figure 5-4. Importing the output from the job.

13. Go to File > Import Structures
14. Navigate to the provided files and choose via Section_05 > nanoreactor_nitrosamine > nanoreactor_nitrosamine-products.maegz
15. Click Open

Figure 5-5. Output after running the job or importing from provided files.

A new entry group is added to the entry list. The group contains 66 entries.

Note that if you performed the calculation yourself, the exact number of output structures may vary due to random seeding in the metadynamics simulations.

Feel free to visualize any of the entries in the workspace.

Figure 5-6. Opening the Nanoreactor Results panel.

More quantitative analysis can be performed in the results panel:

16. Use the WAM (workflow action menu) button () to access the Nanoreactor Results panel
    • Alternatively, go to Tasks > Materials > Quantum Mechanics > Nanoreactor > Nanoreactor Results and use the Load selected entries button to load the entire entry group into the panel
    • The Nanoreactor Results panel opens

Figure 5-7. Viewing the diazonium product.

17. Go to DFT//xTB Energy tab
18. Increase Plot structures within to 100.0 Kcal/mol of the lowest energy structure
    • The relative energy tab sorts the products based on DFT//GFN2-xTB thermodynamics. Specifically, electronic energy is calculated with DFT and thermal corrections are calculated with GFN2-xTB.
19. Hover the mouse over data points to visualize a 2D sketch of the products.
    • The 18th product is the diazonium species which is a known DNA alkylating agent as mentioned in the Introduction. Proceed to visualize the various structures.
20. Close the Nanoreactor Results panel