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View Hypothesis Workbench


Exclude/OR QuickTool

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Introduction to the Exclude/OR QuickTool

 The View Hypothesis workbench is for defining hypothesis features-all of which must be satisfied for the hypothesis to be satisfied as a whole. The relationship between features involves the logical AND operator; when you use a hypothesis containing such features to search a database, a compound must satisfy all of them to qualify as a match or hit.

You can, however, specify chemical characteristics in a hypothesis feature. The Exclude/OR QuickTool allows you to generalize a feature by specifying a collection of "rules" (logical OR definitions). In addition, for each rule you can optionally specify a set of "exceptions" (exclusions) to it. For example, with the Exclude/OR QuickTool you can extend the definition of a feature in a hypothesis so that it identifies structures that can select for

Parts of the Exclude/OR QuickTool

 The Exclude/OR QuickTool consists of two columns of 3D workspaces. The workspaces at the top are for specifying the chemical definitions or rules for a generalized feature. The two top workspaces are called OR windows, because a compound matching any of the specifications defined constitutes a match. Beneath each OR window is an exclusion window in which you can define exceptions to the rule that is defined in the OR window. See the diagram below.

Although you can display only two rules at a time, you can extend the number of columns to specify as many feature definitions as you need. Similarly, you can extend the number of exclusion windows in each column to define as many exceptions as you need, but only two at a time are visible.

The Exclude/OR QuickTool displays four windows at all times: two OR windows at the top of two columns and one exclusion window for each OR window. When there are more than two OR windows or exclusion windows, you can use the scroll bars to display different windows containing different components of the feature.

All windows in the QuickTool have the editing functionality of the View Hypothesis workbench. You can zoom and rotate fragments and functions in the windows as in other workspaces. As with the View Hypothesis workbench, you can bring hypotheses into a window either by selecting fragments and functions from the Feature Dictionary or by dragging compounds or hypotheses from any shelf into the window.

The Exclude/OR QuickTool has menus and a Toolbox very similar to the View Hypothesis workbench. Note that when you use a command from the QuickTool menus or from the Toolbox, the command or tool applies only to the selected window as discussed in "Selecting Windows".

The Exclude/OR QuickTool differs from the View Hypothesis workbench as follows:

How to Use the Exclude/OR QuickTool

 The following discussion explains how to use the Exclude/OR QuickTool. To clarify the explanation, each step in the general procedure is described first. Immediately following the general step is a specific step illustrating how to build a feature specification for an aliphatic amino acid that is not contained in the peptide sequence Ala-Gly-Ala-Gly or Ala-Cys-Ala. For the purpose of the example, alanyl, glycyl, isoleucyl, leucyl, and valyl are considered aliphatic amino acid residues. Our rules for the definition in the example are

The exceptions to the "Ala rule" are that the Ala cannot be in Ala-Gly-Ala-Gly or Ala-Cys-Ala.

Although the Feature Dictionary includes a predefined aliphatic amino acid fragment (Aliphatic AA), describing how to build such a specification demonstrates the functionality of the Exclude/OR QuickTool.

Setting Up for the Example

If you want to work through the example, do the following:

  1. Open a View Hypothesis workbench or clear the display if one is already open.

  2. From the Feature Dictionary, add Alanyl to the workspace. In our example of building an aliphatic amino acid, the alanyl represents an alanyl residue embedded in a peptide chain or located at either terminus.

  3. Select the nitrogen and use the Set Atom Specification tool in the Toolbox to bring up the Atom Specification Editor dialog box. Leave Aliphatic and Exocyclic turned on and click on Endocyclic and Bridgehead to turn them off. Set the lone pair count to 0,1 and the hydrogen count to 1,2. Then select OK.

Note: For an alanyl at the C terminus or embedded in a peptide chain, the lone pair count is 0 and the hydrogen count is 1. For an alanyl at the N terminus, the lone pair count is 1, and the hydrogen count is 2.

Opening the Exclude/OR QuickTool

  1. In the View Hypothesis workbench, select the feature of the hypothesis for which you want to specify rules. The feature can be a piece of connected topology (fragment), a function, or a feature that has already been edited in the Exclude/OR QuickTool. To select the feature, select any of its components.

    If you are working through the example, the nitrogen in alanyl is already selected.

  2. To open the Exclude/OR QuickTool, select the Exclude/OR Edit... command on the Tools menu. The Exclude/OR QuickTool (shown below) opens.

Adding Rules to Generalize a Feature

 You can generalize the definition of a hypothesis feature by specifying additional rules for it. For the example of building an aliphatic amino acid, the selected feature is displayed in the top left window.

  1. From the Feature Dictionary select a function or fragment.

    For example, select Glycyl (i.e., the second rule).

  2. Left-click in the empty right-hand OR window, and the selected function or fragment appears in it.

For the example the first two rules, alanyl or glycyl, are now specified.

Adding More Rules (Append OR Column Command)

 You can add as many rules as you want, as follows:

  1. From the Edit menu, select the Append OR Column command. The Exclude/OR QuickTool temporarily moves the right-hand column and its contents to the left exposing an empty OR column on the right as illustrated below.

  2. Select a function or fragment to add from the Feature Dictionary to specify the next rule.

    For the aliphatic amino acid example, select Leucyl.

  3. Left-click in the new OR window to add the fragment specification. The selected feature appears in the window. You can now see any two of the three columns in the Exclude/OR QuickTool using the horizontal scroll bar at the bottom of the QuickTool.

    If you are working through the example, add the remaining two rules, Isoleucyl and Valyl, in a similar fashion.

    Selecting Windows and Columns

    Each time you select a component in one of the Exclude/OR QuickTool windows, that window and that column becomes selected. You also can select a window by clicking on the appropriate button in the Toolbox, as shown in the figure below.

    When you use a tool or a menu command that affects a window (for example, the Clear Display command in the Edit menu or the Erase tool), the tool or command applies only to the selected window. For commands (such as Append Excluding Entry) that affect all windows in a column, the command applies to the selected column, which is the column containing the selected window.

    Modifying Rules

    With commands from the menus and the tools in the Toolbox, you can modify each of the rules that are defined. For example, you can select an atom and then use the Set Atom Specifications tool to change attributes for the atom. You can erase components by selecting them and then selecting the Erase tool in the Toolbox. You can also use the View and Style menus to change the view and style attributes for the selected window.

    If you are working through the aliphatic amino acid example, use the Set Atom Specifications tool to modify the nitrogen atom in each of the rules so that it has a lone pair count of 0 or 1, a hydrogen count of 1 or 2, and only Aliphatic and Exocyclic are turned on.

    Narrowing Rules by Specifying Exceptions

    After defining a series of rules, you can refine each rule by specifying exclusions; that is, exceptions that compounds matching the hypothesis must not contain. For example, you can define a feature that allows an alanyl residue, but not in the peptide sequences Ala-Gly-Ala-Gly or Ala-Cys-Ala.

    What Constitutes a Valid Exclusion Definition

    The topology of an exclusion definition must include the entire topology of the rule it is modifying. That is, the exclusion must be a superset of the topology in the rule. For example, if the rule is a phenyl ring, a naphthyl ring can be stated as an exclusion. If the set of permissible elements for a particular atom in a rule is in the set O, N, or Cl, the set of elements for the corresponding atom in an exclusion must also be one of O, N, or Cl. For every atom and bond, the set of specifications for the exclusion must intersect the specifications for the rule.

    To define an exclusion, use the Set Atom Specifications tool to specify attributes for atoms and the Set Bond Specifications tool to specify attributes for bonds. All the specifications available with these tools apply to exclusion definitions except for Use Atom Stereochemistry and Use Bond Stereochemistry.

    Preparing to Define Exclusions for the Example

    If you are working through the example, do the following:

    1. Select the View Compound QuickTool from the View Hypothesis workbench and create the peptides Ala-Gly-Ala-Gly and Ala-Cys-Ala. For details on how to create a peptide, see "Building Peptides".

    2. When the peptides are completed, select the Return from QuickTool command from the QuickTool menu. The two peptides appear on the View Hypothesis shelf as local compounds and will be used to define exclusions (exceptions) to the alanyl rule of the aliphatic amino acid feature created earlier. You might find it convenient at this point to rename the local compounds by placing the cursor in their icons and typing names that are meaningful to you.

    Steps for Specifying Exclusions

     After defining all of the rules in the OR windows at the top of the columns in the Exclude/OR QuickTool, follow the steps below to specify exclusions for them. For a discussion of the requirements for a valid exclusion, see "What Constitutes a Valid Exclusion".

    1. Ensure that the rule for which you want to specify an exclusion is displayed in an OR window (top of a column) in the Exclude/OR QuickTool. If necessary, use the scroll bar at the bottom of the QuickTool to display the column.

      If you are working through the example, scroll the columns until the alanyl residue appears.

    2. Bring an exclusion definition into the exclusion window below the rule either by selecting a fragment or function in the Feature Dictionary and clicking in the exclusion window, or by dragging and dropping a compound, a hypothesis, or a local object from the shelf of a workbench or lab. A compound or local compound dropped in the Exclude/OR QuickTool is automatically converted to a hypothesis and displayed in the exclusion window.

      To continue with the example, drag the local compound Ala-Gly-Ala-Gly from the shelf of the View Hypothesis workbench and drop it on the exclusion window below alanyl in the Exclude/OR QuickTool.

    3. If you drop a feature that is not a valid exclusion in an exclusion window, you will get a warning that the added feature is not a superset of the "allowed" feature, and the dropped function or fragment is displayed. You then must modify the feature to make it into a valid exclusion to the rule at the top of the column.

      For the example, the Ala-Gly-Ala-Gly fragment must be made to represent a terminal or embedded peptide. Select the nitrogen at the N terminus and then use the Set Atom Specifications tool to set the lone pair count to 0,1 and the hydrogen count to 1,2. Also make certain that Aliphatic and Exocyclic are turned on, and then select OK. Note that the exclusion, which is denoted by dotted topology, has been cleared. Click on the Forward button at the bottom of the column to re-establish the exclusion mapping.

      You cannot return from the QuickTool until all features placed in exclusion windows constitute valid exclusion definitions and that each has an indicated exclusion mapping. You can select Cancel QuickTool from the QuickTool menu at any time, but all your work will be lost.

      Displaying Exclusion Mappings

      The Status Area at the top left of the Exclude/OR QuickTool initially reports the total number of ways that the definition of the rule maps to the definition of an exclusion that you specified. In the example, the terminal portion of the Ala-Gly-Ala-Gly exclusion that matches the alanyl rule is displayed in the Dots style as shown below.

      When you step through the mappings, the Status Area provides a display of the form m/n, where m is the current mapping displayed in dots, and n is the total number of mappings. Some of the mappings may derive purely from symmetry; other mappings result from topological correspondences between the definitions of the rule and its exclusion. As an example of mappings resulting from symmetry, a methyl group in a rule can map in six different ways to a methyl group in an exclusion, since each combination of hydrogen-to-hydrogen mapping is considered.

      To examine different mappings:

      Adding More Exclusions (Append Excluding Entry Command)

      1. Select a window in the column to which you want to add another exclusion.

      2. From the Edit menu, choose the Append Excluding Entry command to display a new, empty exclusion window at the bottom of the selected column. The previous exclusion window scrolls up so that you can see the new exclusion window. The OR window always displays the rule for which you are defining an additional exclusion. You can scroll up and down to see the different exclusion windows by using the scroll bar at the left or right of the column. If you scroll back over an empty exclusion window, you will need to use the Append Excluding Entry command again.

      3. Place an exclusion definition in the empty window, either by selecting a fragment or function from the Feature Dictionary or by dragging and dropping a compound or hypothesis from a shelf.

        If you are working through the example, drag the Ala-Cys-Ala local compound from the shelf of the View Hypothesis workbench and drop it into the empty exclusion window. As you did previously, select the nitrogen at the N terminus and use the Set Atom Specifications tool to set the lone pair count to 0,1 and the hydrogen count to 1,2. Also make certain that Aliphatic and Exocyclic are turned on, and then select OK.

      4. Reset the exclusion mapping by clicking on the Forward button.

        You can continue adding exclusions by using the Append Excluding Entry command in the Edit menu.

      Displaying All the Exclusions for a Rule

       For each rule that is defined, you can view each of the exclusions specified for it by scrolling through the exclusion windows. However, you also can get an overview of all the exclusions for a rule in a single window, as follows:

      1. Select the column you want to view.

      2. Select Show Exclusion Column... from the Tools menu to display the Overview Display window with the rule in a square and all of its exclusions outside the square. You cannot do any editing in this window, but you can get an overview of the overall rule. This display summarizes the chemistry involved in one OR definition.

      3. Select Return to dismiss the overview display.

      Representation of a Set of Rules

       After defining rules and any exceptions to them, when you return from the Exclude/OR QuickTool a yellow sphere labelled OR appears in the View Hypothesis workspace. This composite OR feature is a visual representation of all of the rules and their respective exclusions. A composite OR feature can be used as a hypothesis by itself, or it can be merged with other features into a hypothesis. However, in this form the composite OR feature cannot be used in any geometric manner such as in the definition of a geometric object or a constraint. To use the composite OR feature geometrically, you must summarize its geometric representation by defining one or more associations as described in the next section.

      Association Editor

      Summarizing Rules: Linking Common Components by Defining Associations

      In our aliphatic amino acid example, the yellow sphere representing the composite OR feature defines a fragment that can be an alanyl (not in Ala-Gly-Ala-Gly and Ala-Cys-Ala), glycl, leucyl, isoleucyl, or valyl residue. Suppose that you want to add a distance constraint from this feature to some other fragment or function in a hypothesis. To which part of the alanyl, glycyl, leucyl, isoleucyl, or valyl substructure should the distance constraint be attached? What is needed is an atom that is common to all of the rules. For example, we could attach it to the alpha carbon or the carbonyl oxygen in each of the respective amino acid residues.

      Setting associations provides a summary of a complex specification by matching corresponding atoms and bonds in each rule so that you can define geometrical relationships (such as geometrical objects and constraints) at the workbench level. Not all of the topology in each rule has to appear in the summary, only the parts that are relevant to the chemistry that is being expressed. Summarized topology can be used to specify geometrical relationships involving components common to the composite OR feature or between other features in a hypothesis. You can set and view associations using a separate tool that summarizes all of the common components of the collection of rules in the feature as described in the following sections.

      Summarizing a Collection of Rules by Setting Associations

      The following procedure uses a composite OR feature (an aliphatic amino acid hypothesis fragment that contains alanyl not in Ala-Gly-Ala-Gly and Ala-Cys-Ala, glycyl, valyl, leucyl, and isoleucyl residues as rules). If you have built this feature by working through the procedures in the preceding examples and have returned from the Exclude/OR QuickTool, you can continue with the example by selecting the yellow OR sphere in the View Hypothesis workbench and then selecting the Exclude/OR Edit... command from the Tools menu to reopen the Exclude/OR QuickTool.

      To Set Associations to Summarize a Collection of Rules

      1. From the Tools menu in the Exclude/OR QuickTool, select the Set Associations... command to display the Association Editor window. Each rule in the composite OR feature is displayed. The yellow sphere that represents the composite OR feature is displayed inside a square as shown in the illustration that follows. The arrangement of the rules and the yellow square depends on how many rules are present.

      2. In the Association Editor, for each rule, extend select a common object to be associated (summarized).

        If you are working through the example, first extend select the oxygen atom in each of the alanyl, glycl, leucyl, isoleucyl, and valyl rules.

      3. Select the Add Association button at the right of the Association Editor window. The yellow sphere inside the yellow square is replaced by an atom specification with colored netting to indicate an association of components (i.e., a summary) in the composite OR feature.

        For the example, select the Add Association button; the association (summarized atom) exclusively represents an oxygen atom in the alanyl, glycl, leucyl, isoleucyl, or valyl rules, so it is red.

      4. To see which components are included in a summary, left-click on the atom specification inside the yellow square. As shown in the illustration that follows, Catalyst extends lines from the atom specification to each of the associated atoms in the rules of the feature that have been summarized.

      5. You can summarize more of each rule by setting more associations: extend select corresponding objects in each of the rules and then select the Add Association button. Each object for which you have added an association is displayed in the current summary of the composite OR feature, so you can see that the component has a defined association.

        For our continuing example, extend select the double bond attached to the oxygen in each rule and then select the Add Association button. (You might need to rotate some of the rule topologies to see the double bond.) The double bond and the carbon atom both are included in the summary and displayed in the current summary of the composite OR feature, as shown below.

        To complete the example, add associations for the C-CA and CA-N bonds. The quickest way to do this is to select the bond to the alpha carbon in each rule, and then select the Add Association button. Next, select the C-N bond, and then select the Add Association button. In both cases, the bonds and the remaining unassociated atom at the end of the bonds are added to the association set and displayed. The completed example is shown below.

        To add an atom or bond from a new rule to a previously summarized association, select an atom or bond that is part of the association, and then extend select the new corresponding component. Finally, select the Add Association button.

        Note that you must add each common component to an association separately. Also, you can only add a bond to an association if at least one of the atoms at the end of the bond is already in the association. When you set an association for a bond, the other atom to which the bond is connected is automatically added to the association, if it is not already included.

        To Display Associations (Correspondences in a Summary)

        You can display associations in the Association Editor window as follows:

        To Delete an Association

         To delete an association, select the component to have its association removed, and then click on the Delete Association button as follows:

        Returning from the Association Editor

         To return from the Association Editor, select the Return button at the bottom of the window. Remember that all valid associations must include one corresponding component in each rule before you can return from the Association Editor. A message will be displayed if all associations are not properly defined when you try to return to the Exclude/OR QuickTool. If the associations are defined properly, the Association Editor disappears when you select Return.

        Associations are added as you make them, so there is no Cancel button in the Association Editor. To leave the editor without saving your changes, you must use the Delete Association button to remove the associations that you have added but want to discard. Alternatively, you can select Cancel QuickTool from the QuickTool menu and abandon all changes made in both the Association Editor and in the Exclude/OR Editor.

        Returning From the Exclude/OR QuickTool

        When you are satisfied with the changes made in the Exclude/OR QuickTool, select the Return from QuickTool command in the QuickTool menu. To leave the Exclude/OR QuickTool without keeping any of the changes you made, select the Cancel QuickTool command from the QuickTool menu.

        When you return to the View Hypothesis workbench, what you see depends on what was selected when you opened the QuickTool and what associations have been defined for the composite OR feature, as follows:

        Using Composite OR Features in Constraint Definitions

         When you have defined associations in a composite OR feature, you can define geometric constraints in the View Hypothesis workbench using the summarized objects. Continuing with our aliphatic amino acid example, if you add a location constraint to the nitrogen, you are effectively adding a location constraint to the nitrogen in each of the rules; that is, whichever happens to apply. Similarly, if you add a distance constraint from the alpha carbon to some other fragment in the hypothesis, you are effectively adding a distance constraint from the alpha carbon in each of the rules, whichever happens to apply.

        Editing Composite OR Features That Have Been Summarized

        When you define constraints that include a composite OR feature and subsequently modify the composite OR feature in the Exclude/OR QuickTool by changing its rules or its associations, the appearance of the modified composite OR feature might be different when you return to the View Hypothesis workbench. First, if any constraints involve any component in the modified OR feature, they will be deleted. In addition, any changes to the associations (i.e., the summary) for the composite OR feature will be reflected in its appearance in the View Hypothesis workspace.

        Again, using the aliphatic amino acid example, suppose that you want to define a distance constraint from the oxygen in the aliphatic amino acid composite OR feature to a phenyl fragment. The procedure follows:

        1. Ensure that the aliphatic amino acid OR feature is displayed in the View Hypothesis workbench. Return from the Exclude/OR QuickTool, if necessary.

        2. From the Feature Dictionary select Phenyl, and then left-click in the View Hypothesis workspace near the aliphatic amino acid OR feature. The phenyl fragment appears.

        3. Select the oxygen specification in the aliphatic amino acid OR feature and extend select the centroid of the phenyl.

        4. From the Constraints menu, select Define Constraint and then Distance from its submenu.

        5. In the Constraint Tolerance dialog box, define a distance constraint of 4 to 8 angstroms.

        6. Now select the aliphatic amino acid OR feature and reopen the Exclude/OR QuickTool by selecting Exclude/OR Edit... from the Tools menu.

        7. Select Set Associations... from the Tools menu in the Exclude/OR QuickTool.

        8. In the summary of the composite OR feature (in the yellow square), select the bond between the two carbons and then select Delete Association. The bond disappears in the composite OR feature (see below). Notice that deleting the association does not change any of the rules. It only removes the bond from the summary of the composite OR feature.

        9. Return to the Exclude/OR QuickTool and notice that there are no differences here as a result of deleting the bond association.

        10. Return to the View Hypothesis workbench. The display of the composite OR feature is the same as it was in the Association Editor, as shown below. Notice also that the distance constraint between the OR feature and the phenyl has disappeared. When you edit a composite OR feature in the Exclude/OR QuickTool or the Association Editor, all constraints involving any of the summarized components in the edited feature are deleted.

        11. Now you can redefine the distance constraint between the phenyl fragment and the oxygen specification in the OR feature.


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        Last updated April 18, 1996 at 03:04pm PDT.
        Copyright © 1999, Molecular Simulations Inc. All rights reserved.