Defining QM and MM regions in QSite

Tutorial Created with Software Release: 2023-3
Topics: Quantum Mechanics, Small Molecule Drug Discovery
Products Used: QSite

Tutorial files

1.5 MB
This tutorial is written for use with a 3-button mouse with a scroll wheel.
Words found in the Glossary of Terms are shown like this: Workspacethe 3D display area in the center of the main window, where molecular structures are displayedthe 3D display area in the center of the main window, where molecular structures are displayed

 

Tip: You can hover over a glossary term to display its definition. You can click on an image to expand it in the page.
Abstract:

 

This tutorial demonstrates the common task of selecting QM (quantum mechanics) and MM (molecular mechanics) regions in the QM/MM program QSite. This task must be performed at the outset of each Qsite calculation.

 

Tutorial Content

  1. Introduction

  1. Creating Projects and Importing Structures

  1. Defining QM-MM regions

  1. Conclusion and References

  1. Glossary of Terms

1. Introduction

The QSite program performs QM/MM calculations, that is, calculations in which a region of the molecule is treated with QM (quantum mechanics) method and the rest of the molecule is treated with an MM (molecular mechanics) method. The regions interact via a QM/MM interface. Usually, the QM region is smaller than the MM region, and represents the most important part of the molecule (for example the active site of a protein). As MM methods are computationally significantly cheaper than the more accurate QM methods, treating the whole molecule at the QM/MM level has a benefit of working with a large, untruncated molecule, describing its most interesting region accurately and at the same time keeping computational costs low. QM/MM methods are normally used for modeling enzymatic reactions or non-covalent binding of small molecules to proteins. In order to start any calculation with QSite you must define the QM and MM regions of your molecule.

In this tutorial we will be using a small molecule/protein complex similar to that used in the research paper mentioned below:

R. Lonsdale and M. T. Reetz, “Reduction of α,β-Unsaturated Ketones by Old Yellow Enzymes: Mechanistic Insights from Quantum Mechanics/Molecular Mechanics Calculations”, J. Am. Chem. Soc., 2015, 137, 14733−14742.

In this paper the authors studied the oxidation of a 2-cyclohexen-1-one into cyclohexanone, catalyzed by the so-called old yellow enzyme YqjM from bacterium Bacillus subtilis. The complex details of preparing the small molecule/protein complex described by the authors are not important to follow for this tutorial, and instead, we will be working with a molecular system that has already been prepared for you for the task of selecting its QM and MM regions.

2. Creating Projects and Importing Structures

At the start of the session, change the file path to your chosen Working Directorythe location that files are saved in Maestro to make file navigation easier. Each session in Maestro begins with a default Scratch Projecta temporary project in which work is not saved, closing a scratch project removes all current work and begins a new 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 Directorythe location that files are saved using File > Import Structures, and are added to the Entry Lista simplified view of the Project Table that allows you to perform basic operations such as selection and inclusion and Project Tabledisplays the contents of a project and is also an interface for performing operations on selected entries, viewing properties, and organizing structures and data. The Entry Lista simplified view of the Project Table that allows you to perform basic operations such as selection and inclusion is located to the left of the Workspacethe 3D display area in the center of the main window, where molecular structures are displayed. The Project Tabledisplays the contents of a project and is also an interface for performing operations on selected entries, viewing properties, and organizing structures and data 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

Figure 2-1. Change Working Directory option.

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

Figure 2-2. Save Project panel.

  1. Go to File > Save Project As
  2. Change the File name to Qsite-QM-MM-regions
  3. Click Save
    • The project is now named Qsite-QM-MM-regions.prj

 

3. Defining the QM-MM Regions

3.1 Import Structures

Figure 3-1. The molecular system from the 1Z44-prepared.mae file.

  1. Go to File > Import structures
  2. Select 1Z44-prepared.mae
  3. Click Open
    • The protein in complex with some small molecules is displayed in the Workspacethe 3D display area in the center of the main window, where molecular structures are displayed
    • The protein is rendered in helices, beta-sheets, and loops, with the ligands shown in tube representation

This structure has been prepared using the Protein Preparation Workflow. The preparation procedure used in the paper was more complex, but ours is sufficient for this tutorial. Please see the Introduction to Structure Preparation and Visualization tutorial for more information about this process.

 

Figure 3-2. View of the protein sequences in the Multiple Sequence Viewer panel, showing that chains A and B have the same sequences.

  1. Click Tasks, and type multiple sequence viewer
  2. Select Multiple Sequence Viewer
    • The Multiple Sequence viewer panel opens
    • Residues are colored by residue type to enable easier visual comparison
    • Chains A and B are identical

Figure 3-3. View of the interaction between the ligand of one chain (gray) and an end of another chain (white).

Since both chains are the same, and the small molecules bound to these chains are also the same, it seems possible to simplify the QM/MM calculation by modeling one part of the system and deleting the other. However, this is not a good idea. By examining the boundaries between the two symmetrical parts of the system, we can see that Chain B of the protein lies close to and interacts with the ligand of Chain A. By removing one of the chains, we run the risk of disturbing the region around the ligand which is of greatest interest. It is therefore best to leave both chains intact when modeling this particular system with QSite.

Figure 3-4. View of the options in the Style palette to customize the representation of the complex, in the Workspace.

We will now render the complex using the Style palette, to give a clearer and more detailed view of the atoms and residues. This will help us while defining our QM and MM regions.

 

  1. Go to Style > Display atoms
  2. In the Style palette, go to Color Atoms > Element + Custom Ligand
    • This colors all the atoms in the protein according to the respective elements and the ligand is displayed in a different color, making it discernible from the remaining residues
  3. In the Style palette, click on Remove ribbons from selected residues

Figure 3-5. View of the Workspace centered on the 2-cyclohexen-1-one ligand. The coloring style followed is Element + Custom Ligand; atoms are colored as per the element and the ligand is shown with green carbons.

  1. Double click on the 2D representation of 2-cyclohexen-1-one for Chain A in the Workspacethe 3D display area in the center of the main window, where molecular structures are displayed

 

You can also press the L key on the keyboard

 

Note: If the 2D representation is not turned on by default, you can do so by choosing Window > 2D overlay

3.2 Select QM and MM regions

Once our structure has been imported and rendered, we are ready to select the QM and MM regions of our system.

Figure 3-6. Locating the QSite panel in the Tasks widget.

  1. Go to Tasks > type QSite
  2. Choose QSite
    • The Qsite panel opens with the QM settings tab displayed

Note: You can also access the panel by navigating to Tasks > Browse > Other Applications > Qsite

Figure 3-7. The QSite panel.

The level of theory for our calculation is set at the top of the QSite panel. In our case the level of theory is DFT, and the density functional is B3LYP

 

Figure 3-8. Activate picking free ligand/ion in the QSite panel, for including small molecules bound to the protein in the QM region.

The first part of the system to include in the QM region is the ligand bound to the protein

 

  1. Pick Free ligand/ion from the dropdown
    • This option is used when including a small molecule or ion (not covalently attached to the protein) in the QM region

Figure 3-9. Inclusion of 2-cyclohexen-1-one in the QM region.

  1. Click on any atom of 2- cyclohexen - 1- one in the Workspacethe 3D display area in the center of the main window, where molecular structures are displayed
    • All the atoms in the molecule are highlighted, and an entry corresponding to this free ligand/ion appears in the QSite panel

 

You can use the Delete button to remove any entry,  that has been included by mistake, from the table

Figure 3-10. Options for selecting the QM region in the QSite panel.

Other parts of the system that we would include in the QM region are the residue TYR169 and the flavin cofactor. Both these parts are covalently attached to protein’s chain A.

 

  1. Pick Side Chain from the dropdown

Side chain cuts can be made in any peptide residue other than alanine, glycine, and proline

 

The flavin fragment attached to the protein is not a standard amino acid residue and must be selected using the hydrogen cap method.

Figure 3-11. Selecting using the Hydrogen cap in the flavin fragment.

  1. Click on any atom of the residue, TYR 169 of chain A. (very close to 2 - cyclohexen - 1 - one.)
    • The residue is highlighted in the Workspacethe 3D display area in the center of the main window, where molecular structures are displayed and added to the QM region table in the QSite panel
  1. Pick Hydrogen Cap from the dropdown
  2. In the Workspacethe 3D display area in the center of the main window, where molecular structures are displayed, click first on the carbon atom bonded to the CH2 group (atom number 5293) and then on the carbon atom of the OH group (atom number 5294)
  • A 3D arrow appears in the Workspacethe 3D display area in the center of the main window, where molecular structures are displayed and the entry corresponding to the Hydrogen Cap is created in the QM panel, indicating the atoms that mark the QM and MM region respectively
  • The origin of the arrow is at the latter carbon atom which is the beginning of the QM region and points to the former carbon atom which is in the MM region
  • The rest of the flavin fragment now belongs to the QM region

To find a specific atom number in the Workspacethe 3D display area in the center of the main window, where molecular structures are displayed, it can be useful to use control-F and use the Find: Atom search bar that appears.

Figure 3-12. All the 60 atoms in the QM region, shown in red in the Workspace.

  1. Click the Update QM Region at the bottom of the panel
    • The QM atoms are now marked in red in the Workspacethe 3D display area in the center of the main window, where molecular structures are displayed

 

Figure 3-13. The basis set for all atoms in the QM region is shown in the QM Basis tab.

  1. Click on the QM Basis tab
    • The basis set  function, lacvp* is assigned to the atoms in the QM region

 

Every atom that is not in the QM region will be treated at the MM level.

  1. Click Run
    • This job will take ~ 6-7 hours to run on a 2 CPUs
    • To save time, we will look at pregenerated results

You can change the basis set for any atom by clicking on the corresponding row in the table and then selecting the appropriate basis set for that atom from the dropdown on the right.

Figure 3-14. QSite job output.

  1. Go to File > Import Structures  and choose qsite_1.01.mae
  2. Click Open
    • The QSIte results are 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 qsite_1.out file contains information about various energetic contributions to the system, as well as the set-up of the QM and MM regions.

4. Conclusion and References

This tutorial explained the minimal necessary setup of the protein-ligand system required to start working with the QSite program. We introduced the QSite panel selected of the QM region using different QM selection methods: free ligand/ion, side chain, and hydrogen cap. Such operations have to be performed in every QM/MM calculation, and it is important to become familiar with them.

For further reading:

 

 

5. 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