Difference between revisions of "Tutorial:Glide"

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   The Settings button opens the Receptor Grid Generation - Job Settings dialog box.
 
   The Settings button opens the Receptor Grid Generation - Job Settings dialog box.
  
===Ligand bound===
+
==Choice of Ligand Databases==
  
===Known pocket but without no ligand bound===
 
  
==Choice of Ligand Databases==
+
The NCC725 database; click
 +
  [http://theyanglab.org/doc/NCC-106_Shipment_11210.sdf NCC]
  
 +
The CWRU-SMDD database; click
 +
  [http://theyanglab.org/doc/CWRW_smdd_NT1299-1.sdf SMDD]
  
=== SDF ===
+
==VSW==
{{Infobox file format
+
| name = ctab
+
| extension = <tt>.sd</tt>, <tt>.sdf</tt>
+
| mime = chemical/x-mdl-sdfile
+
| owner =
+
| creatorcode =
+
| genre = [[chemical file format]]
+
| container for =
+
| contained by =
+
| extended from =
+
| extended to =
+
}}
+
  
SDF is one of a family of chemical-data file formats developed by MDL; it is intended especially for structural information. "SDF" stands for structure-data file, and SDF files actually wrap the molfile ([[#Molfile|MDL Molfile]]) format. Multiple compounds are [[delimiter|delimited]] by lines consisting of four dollar signs ($$$$). A feature of the SDF format is its ability to include associated data.
+
The Virtual Screening Workflow is designed to run an entire sequence of jobs for screening large collections of compounds against one or more targets. The workflow includes ligand preparation using LigPrep, filtering using ligfilter on QikProp properties or other structural properties, and Glide docking at the three accuracy levels, HTVS, SP, and XP. The design allows you to choose which of the stages to include in any run, and which selection of results from one stage are passed on to the next.
  
Associated data items are denoted as follows:
+
The full workflow includes three docking stages.  
<code>
+
>  <Unique_ID>
+
XCA3464366
+
 
+
>  <ClogP>
+
5.825
+
+
>  <Vendor>
+
Sigma
+
+
>  <Molecular Weight>
+
499.611
+
</code>
+
+
Multiple-lines data items are also supported. The MDL SDF-format specification requires that a hard-carriage-return character be inserted if a single line of any text field exceeds 200 characters.  This requirement is frequently violated in practice, as many [[SMILES]] and [[InChI]] strings exceed that length.
+
  
==VSW==
+
The first stage performs HTVS docking.
 +
 
 +
The ligands that are retained are then passed to the next stage, which performs SP docking;
 +
 
 +
the survivors of this stage are passed on to the third stage, which performs XP docking.
 +
 
 +
At each stage you can decide how many ligands are kept, and whether all the ionization and tautomeric states of each ligand are kept, or only some.
 +
 
 +
 
 +
===Virtual Screening Workflow Panel===
  
 +
The Virtual Screening Workflow panel enables you to set up and run jobs to screen ligands against one or more targets. The workflow includes ligand preparation, filtering, and up to three docking stages with Glide, progressing from HTVS to SP to XP docking. For docking to multiple targets (ensemble docking), you can specify docking score offsets for each target.
  
The full workflow includes three docking stages. The first stage performs HTVS docking. The ligands that are retained are then passed to the next stage, which performs SP docking; the survivors of this stage are passed on to the third stage, which performs XP docking. At each stage you can decide how many ligands are kept, and whether all the ionization and tautomeric states of each ligand are kept, or only some.
+
To open this panel,  
 +
choose
 +
    Tasks → Applications → Glide → Virtual Screening Workflow. in the Task Tool.

Latest revision as of 15:47, 15 September 2017

(Click for lab website)

Download

To download the Schrödinger software, please visit the Download Center (login required):

  http://www.schrodinger.com/downloadcenter/

As of September 8, 2017, the current release version is 2017-3 (just released yesterday!).


Just in case, I have a copy downloaded already for Windows and MacOS, which will be provided either by USB key or CD.

It may take a while to download given its large size (about 4GB).

  Now take a break ... while downloading

Installation on your laptop

Before we start, make sure you are within the Case campus network, either by connecting through

  CaseWireless

If you are using the CaseGuest wireless, you may need to activate

  VPN

Windows-64

Start by

  1. Double-clicking setup.exe 

Wait for several seconds ... follow the instruction by clicking some 'yes' or 'next' buttons.

  2. "Installing software" ... and wait (depending on how old your laptop is) 

... after several minutes (hopefully), then clicking more 'next' using the default (unless you know what you are doing).

When you see

    "Installation completed successfully!" ... 

STOP and click

   Configure

Since we have been issued a license (installed on a server) , choose

   Add Licenses [I can identify my license server]

Enter Host Name:

   hpctest.case.edu

and Port

   XXXXX

NOTE:

   Replace XXXX with the code provided on-site

Then

   click "Save Server". 

Then check the "Current Status" above. If you see

  "Valid licenses found" 

Congratulations! You are ready to play.

Mac -- License Installation Instructions

After installation, use

  Finder, navigate to Applications → SchrodingerSuites2017-3. 

Then

   Open the Configuration application by double-clicking on it.

Since we have been issued a license (installed on a server) , choose

   Add Licenses [I can identify my license server]

Enter Host Name:

   hpctest.case.edu

and Port

   XXXXX

NOTE:

   Replace XXXX with the code provided on-site

Then

   click "Save Server". 


Then check the "Current Status" above. If you see

  "Valid licenses found" 

you are good to move on.

Getting familiar

Introduction to Structure Preparation and Visualization

This gives an introduction to the Maestro interface and basic visualization tasks. You will learn how to prepare ligand and protein structures, an essential first step for modeling projects.

    using a 3-button mouse with a scroll wheel

Creating Projects and Importing Structures

  Navigate to File > Get PDB

Visualizing Protein-Ligand Complexes

We will explore ways to visualize structures in the Workspace.

Protein Preparation Wizard

The Protein Preparation Wizard will automatically take care of many protein preparation tasks.

To open the Protein Preparation Wizard panel,

  choose Tasks → Protein Preparation and Refinement → Protein Preparation Wizard in the Task Tool, 

or

  click the Protein Preparation Wizard button on the Favorites toolbar (if present).

Import and Process tab

To preprocess the structure, select the desired options, then click

  Preprocess 

The options are as follows:

  • Align to—Align the protein structure to that of another protein. You can choose the other protein by selecting an entry in the Project table (Selected entry) or by specifying a PDB ID for a structure from the PDB. The alignment is done with the Protein Structure Alignment tool that is on the Tools menu—see <a href="../prime_help/protein_structure_alignment.html" class="MCXref xref">Protein Structure Alignment Panel</a>.

  • Assign bond orders—This option selects the assignment of bond orders, and performs the same task as Assign Bond Orders on the Tools menu.

  • Add hydrogens—This option adds hydrogens to all atoms in the structure that lack them. The hydrogens are added by the utility applyhtreat.

  • Remove original hydrogens—This option removes the original hydrogens before hydrogens are added, and is only available if Add hydrogens is selected. It ensures that any problems with H atoms are fixed, including nonstandard PDB atom names, which is important for the H-bond optimization tool.

  • Create zero-order bonds to metals—This option breaks bonds to metals, replacing them with zero-order bonds, and adjusts the formal charge on the metal and the neighboring atoms. Sulfurs that interact with metals have their hydrogens removed, if necessary, and are assigned a negative charge. The force fields usually treat metals formally as an ion, without bonds to their ligands.

Review and Modify tab

The goal is to fix Protein Structural Problems if any.

E.g. To add missing side-chain atoms:

 View Problems → Add missing side chains → OK

Refine tab

The goal is to minimizing the Protein Structure.

When you have made your selection of options, click

  Minimize

Receptor Grid Generation

The Receptor Grid Generation panel is used to specify a receptor structure and set up the grid generation job. This job creates the grid files, which represent the active site of the receptor for Glide ligand docking jobs.


To open this panel, choose in the Task tool

  Receptor-Based Virtual Screening → Receptor Grid Generation.

The Receptor Grid Generation panel contains five tabs, which are described in full in separate topics:

  • Receptor tab— Use this tab to define the receptor (by identifying the Workspace ligand, if one is present) and optionally to scale the van der Waals radii of receptor atoms.
  • Site tab— Use this tab to determine the position and size of the volume for which grids will be generated, representing the active site of the receptor.
  • Constraints tab— Use this tab to designate certain receptor atoms (positional/NOE, H-bond/metal constraints) for ligand-receptor interactions that you can then choose to require during docking jobs.
  • Rotatable Groups — Use this tab to specify groups that should be treated as rotatable in the grid generation. These groups are currently restricted to hydroxyls in Ser, Thr, and Tyr, and thiols in Cys.
  • Excluded Volumes— Use this tab to set up regions of space in which the ligand is penalized during docking.

Defining the Receptor

If only the receptor is included in the Workspace, and no ligand is present, you can ignore the Define receptor options.

  • If the Workspace includes both a receptor and a ligand, use these options to pick the ligand molecule. The ligand will be excluded from receptor grid generation. Everything not defined as the ligand will be treated as part of the receptor. The ligand can be identified either as a molecule or as an entry in the Workspace.

  • If you want to use a binding site from a SiteMap calculation, you can do so by treating it as a ligand and including it in the Workspace. Each site from SiteMap is a separate entry. However, the site points in the site are not connected, so the site must be selected as an entry.

To select the ligand, ensure that Pick to identify ligand molecule is selected,

  choose an option from the option menu, then pick an atom in the ligand molecule. 

The ligand (or site) is now distinguished from the receptor. If Show markers is selected, the ligand molecule is marked with green markers. Deselect the option to remove the markers.

Defining the Site Location and Size

The settings in the Site tab determine where the scoring grids are positioned and how they are prepared from the structure in the Workspace.

To make these settings, you need to understand how Glide sets up grids.

Glide uses two “boxes” to organize the calculation:

  • The grids themselves are calculated in the space defined by the enclosing box, or grid box or outer box. This is also the box within which all the ligand atoms must be contained.

  • During the site point search, the ligand center is allowed to move within the ligand diameter midpoint box, or inner box. This box gives a truer measure of the effective size of the search space. However, ligands can move outside this box during grid minimization.

The only requirement on the grid box is that it is big enough to contain all ligand atoms when the ligand center is placed at an edge or vertex of the inner box. Grid boxes that are larger than this are not useful: they take up more space on disk and in memory for the scoring grids, which take longer to compute. The maximum size of the grid box is 80 Å.


If the structure in the Workspace consists of a receptor and the ligand molecule you identified in the Receptor tab, Glide uses the position and size of the ligand to calculate a default center and a default size for the grid box. When you open the Site tab, the Workspace displays the center of the grid box as a set of coordinate axes colored bright green, and the boundaries of the region as a purple wire-frame cube.

If the Workspace includes a SiteMap binding site, you might want to reduce the size of the grid box, because it is likely that the site is larger than defined by a ligand.

   You might also want to specify the center of the box by selection of a few residues from the receptor, as the centroid of the site might not be in the optimal location. 

This is particularly so if the site is not well defined or the site points extend over a broad region.

If the Workspace structure consists of a receptor only, there is no default center for the grid box. The box will not be displayed until you have specified a grid center by selecting residues.

By default, the purple grid box outline and the green axes at the center are displayed when you enter the tab. Deselect Display Box to undisplay the box and its center.


Running Grid Generation Jobs

The controls for starting the job are below the tabs.

  The Settings button opens the Receptor Grid Generation - Job Settings dialog box.

Choice of Ligand Databases

The NCC725 database; click

  NCC

The CWRU-SMDD database; click

  SMDD

VSW

The Virtual Screening Workflow is designed to run an entire sequence of jobs for screening large collections of compounds against one or more targets. The workflow includes ligand preparation using LigPrep, filtering using ligfilter on QikProp properties or other structural properties, and Glide docking at the three accuracy levels, HTVS, SP, and XP. The design allows you to choose which of the stages to include in any run, and which selection of results from one stage are passed on to the next.

The full workflow includes three docking stages.

The first stage performs HTVS docking.

The ligands that are retained are then passed to the next stage, which performs SP docking;

the survivors of this stage are passed on to the third stage, which performs XP docking.

At each stage you can decide how many ligands are kept, and whether all the ionization and tautomeric states of each ligand are kept, or only some.


Virtual Screening Workflow Panel

The Virtual Screening Workflow panel enables you to set up and run jobs to screen ligands against one or more targets. The workflow includes ligand preparation, filtering, and up to three docking stages with Glide, progressing from HTVS to SP to XP docking. For docking to multiple targets (ensemble docking), you can specify docking score offsets for each target.

To open this panel, choose

    Tasks → Applications → Glide → Virtual Screening Workflow. in the Task Tool.