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VISUALIZATION

Introduction to Structure Visualization and PreparationNovember 2014

of 13Introduction to visualization and preparation l

Introduction to Structure Visualization and PreparationCreated with Release 14-4

This tutorial introduces you to the Maestro interface as well as routinely performed visualization tasks. You will learn how to prepare ligand and protein structures for modeling projects. The tutorial is comprised of the following sections:

1. Creating projects and importing structures2. Preparing protein and ligand structures 3. Visualizing protein-ligand complexes

Required File: 1fjs_prep_recep.mae.gz, 1fjs_prep_lig.mae.gz

VISUALIZATION


1. Creating projects and importing structures

Projects (*.prj extension) are the main file format for Maestro. A project file may contain hundreds or thousands of entries; these entries may correspond to imported protein and ligand structures and/or to output of modeling-related tasks. Once a project is created, the project file is automatically saved each time a change is made.

1. Create a Project. Open Maestro by double clicking on the desktop icon. A scratch project is created (Note: scratch projects are not automatically saved!). Press the Save As icon in the Project toolbar (or navigate to Project -> Save As in the menu bar). In the dialog box that appears, type the name “FXa” in the File Name box; press Save (Figure 1). The name of the project at the top of the Maestro window should now be “FXa.prj.”

Figure 1. The Save Project dialog box.

2. Copy Tutorial Files. In the main menu bar, navigate to Help -> Tutorials. In the panel that opens, highlight tutorial 6, corresponding to the Glide Quick Start Guide (Figure 2). Press Copy. Now all tutorial files will be copied into your working directory.


Figure 2. The Tutorials panel.

3. Import Structures. Press the Import button in the Project toolbar. Select files “1fjs_prep_lig.mae.gz” and “1fjs_prep_recep.mae.gz” from your working directory by clicking on one file and then ctrl (or cmd on Mac) clicking on the second file (both files should be highlighted, Figure 3); press Open. Note: *.mae and *.mae.gz files are the default structure file formats for Maestro. However, all common structure file types are supported.

Figure 3. The Import panel.

Imported structures are automatically added to the project table (more on this in subsequent steps). Once structures are added to a project, an entry list appears on the left side of the workspace; this list provides a quick reference to entries contained in the project table. By default only the structure corresponding to the first imported file is included (i.e. visible) in the workspace; however, all imported structures are selected (i.e. highlighted) (Figure 4).


Figure 4. Maestro view after structures are imported. When a structure is imported, it will be included in the workspace as well as in the Entry List (left side of the workspace). If more than one structure is imported simultaneously, then subsequent structures will be added to the project but will not be included in the workspace. Although only the first structure is included (denoted by a red “In’ box), all imported structures are selected (i.e. highlighted in yellow) by default.

Structures can be included or unincluded in the workspace by toggling the “In” box located in the corresponding entry row of the entry list or project table (the box will turn red when an entry is included). Similarly, structures are selected or deselected by ctrl/cmd-clicking anywhere in the corresponding entry row (selected entries are highlighted in yellow).

4. Merge structure entries. Open the project table by pressing the Table icon in the Project toolbar. Ensure that both entries are selected. If you are using a mouse, right click on one of the entries; from the menu that appears, choose “Merge” (Figure 5). Alternatively, navigate to Entry -> Merge from the project table menu.


Figure 5. Merging entries in the project table. The merge function operates on entries that are selected in the project table.

A new merged entry should now appear in the project table. With your mouse or trackpad, double click on the title of the merged entry and change its name to “1fjs_merged”; press Enter to save the change (Figure 6). Include only the merged entry in the workspace in preparation for the next step, then close the project table.

Figure 6. View of the project table after the merged entry has been created and renamed. The

merged entry is included in the workspace, as denoted by the red “In” box.


2. Preparing protein and ligand structures

Structure files obtained from the Protein Data Bank, vendors, and/or other sources often lack necessary information for performing modeling-related tasks. For example, protein structures often lack hydrogens, partial charges, side chains, and/or whole loop regions. Similarity, partial charges, correct protonation (i.e. tautomeric) states, and explicit stereochemistry often need to be assigned to small molecule structures. In this section we will use the Protein Preparation Wizard and LigPrep to fix structure files, making them suitable to use for downstream modeling tasks such as virtual screening.

5. Prepare a protein structure. Access the Protein Preparation Wizard by pressing the Prep Wiz icon in the Project toolbar (or via Tasks -> Protein Prep Wizard, Figure 7). The preparation wizard consists of required processing steps, followed by optional modification and refinement steps. To run the wizard, a single structure must be included in the workspace; this structure can be from the project table or imported directly from the PDB in the first step. The recommended minimal processing tasks are checked; however, you may also wish to fill in missing side chains and/or loops if they are important for subsequent modeling activities. Press Preprocess.

Figure 7. The Protein Preparation Wizard panel.

Once the job is finished, a new, processed entry is added to the project table and replaces the original structure in the workspace.


5B. Refine the prepared structure. Navigate to the Refine tab in the wizard (Figure 8). In this tab the hydrogen bonding network can be optimized by sampling water orientations and flipping Asn, Gln, and/or His side chains. Press Optimize. Once the job is finished a new entry will be added to the project table and the workspace will be updated. Inspect the structure to identify side chains that have been flipped; they will be labeled.

*Note: So as to accurately reflect experimental conditions, you may also wish to adjust the pH, which will change the protonation states of residues and ligands accordingly.

Figure 8. The refinement step of Protein Preparation. In the Refine tab of the wizard, additional optimization steps can be performed.

5C. Minimize the structure (optional). Additional minimization may be performed on the structure by pressing the Minimize button, but it is not necessary.

6. Rename the refined structure. Double click on the title of the last entry in the entry list; rename it “1fjs_refined.”

7. Split the refined structure into separate ligand and protein entries. Select the refined structure and right click on it; from the menu that appears, select Split -> Into Ligands, Water, Other (Figure 9). Two new entries will appear in the project table for the ligand and protein.


Figure 9. Splitting entries in the project table.

8. Prepare a small molecule structure. Select the entry “1fjs_refined_ligand.” From the main menu bar, navigate to Tasks -> Ligand Preparation; the LigPrep panel will appear (Figure 10). From the Use structures from drop-down menu, select Project Table (selected entries). Ensure that the Desalt and Generate Tautomers boxes are checked, and change the Stereoisomers option to Determine chiralities from 3D structure. Change the Job name to “1fjs_ligprep”; press Run.

Figure 10. The LigPrep panel.

Once the job finishes, a new group will be created in the project table containing two new entries.


3. Visualizing protein-ligand complexes

9. Apply a workspace style. Include the entry “1fjs_refined” in the workspace. Press the Apply button located in the Style toolbar. In the default workspace style, the protein is represented as a ribbon, with residues near the ligand depicted as lines. Ligand molecules are rendered as ball and stick (Figure 11). If the view in the workspace is not centered automatically on the ligand then press ‘L” to recenter.

Figure 11. Workspace style rendering.

10. Visualize Hydrogen bonds. Press the HBonds button located in the Measurements toolbar; choose Display. Yellow dotted lines representing hydrogen bonds between the ligand and receptor will appear (Figure 12).

Figure 12. Hydrogen bond visualization.


11. Visualize van der Waals contacts. Press the Contacts button located in the Measurements toolbar; choose Display. Contacts within potential clashing distance, aka “ugly” and “bad” contacts, will be colored red and orange respectively (Figure 13). Thresholds for “ugly” and “bad” are set to .75 and .89 respectively; these values correspond to the ratio of the distance between the two atoms and the sum of their van der Waals radii.

Figure 13. Visualizing van der Waals contacts

12. Create a receptor surface. Turn off Hydrogen bond and van der Waals contacts by unchecking Display. Press the Surfaces button in the Style toolbar. In the panel that appears, uncheck the Create Ligand Surface box, set the transparency to 0, and change the color scheme to Electrostatic Potential. Press OK. An electrostatic surface* will now appear around the ligand (Figure 14). *Note: Electrostatic surfaces can only be created for prepared structures!

Figure 14. Surface generation.


Adjust the opacity and color scheme of the surface by clicking and holding down the Surfacesbutton. From the menu that appears choose Manage; the Manage Surfaces table will appear (Figure 15). Similar to entries in the project table, surfaces can be included or unincluded in the workspace by toggling off and on the In button.

Figure 15. The surface management panel.

Press the Display Options button. Under Color Scheme, change the Minimum and Maximumvalues to -0.1 and 0.1 respectively; press OK. The intensity of the surface colors is increased(Figure 16).

Figure 16. The electrostatic surface after the color ramp is changed.


13. Generate a 2D interaction diagram. Press the Ligand Interaction button located in the Project toolbar. A new window will appear with a two-dimensional rendering of the receptor-ligand interactions (Figure 17). If the Sync with 3D box is checked then rotation of the workspace view will change the 2D view accordingly, and vice versa. Press the cleanup (green arrow) button on the left side to optimize the view. Images can be saved via File -> Save Image.

Figure 17. 2D Ligand Interaction diagram.


14. Save an image of the workspace. Close the 2D ligand interaction panel. Create an image of the workspace view by navigating to Workspace -> Save Image. In the panel that appears (Figure 18), press Options >> to see more advanced settings. Here you can specify the image size and quality, in terms of DPI, and choose to create a transparent background and/or smooth the image.

Figure 18. Saving an image.

Figure 18. Saving an image.

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