Build Homology Model Panel

Build a homology model for a single chain or a multimer.

To open this panel, do one of the following:

  • Click the Tasks button and browse to Protein Preparation and Refinement → Homology Modeling
  • Click the Tasks button and browse to Biologics → Homology Modeling

You can also choose Build Homology Model from the Other Tasks button menu in the Multiple Sequence Viewer/Editor Panel.

  • Using
  • Features
  • Additional Resources

Using the Build Homology Model Panel

Building a homology model using this panel is done in a series of steps. Each step involves one main action, which can be completed by clicking the link in the step and performing any resultant actions, such as choosing a sequence or a template. As the tasks at each step are completed, a green check mark appears to the left of the step name. Steps that are completed may be marked as completed by clicking the green check mark. They are made unavailable (dimmed), to indicate that they do not need to be done again. If you want to redo a step that's unavailable, click the green check mark again.

To write out the input file and a script for running the job from the command line, click the arrow next to the Settings button and choose Write. For information on command usage and options, see prime Command Help.

Build Homology Model Panel Features

Use option menu

Choose an option for the number of templates to use. This determines the type of homology model used. The steps listed in the panel depend on the choice from this menu.

  • 1 target, 1 template—build a single chain model from a single template. This choice requires high identity between the target and template sequences.

  • Multiple templates (chimera)—build a model of a single chain with multiple templates, each of which is used for part of the chain.

  • Multiple templates (homomultimer)—build a model of a homomultimer, from templates for each chain. These templates must be imported into the tab, and the structures for each template chain must already be in the correct spatial arrangement to build the multimer. This usually means that the template is itself a homo-multimer, but it could also be a hetero-multimer with a high sequence identity between the chains.

  • Multiple templates (consensus)—build a model of a single chain that is a consensus derived from multiple templates. Each alpha carbon is placed at the position where the largest number of templates places that carbon.

  • Multiple View tabs (heteromultimer)—build a model of a heteromultimer, from templates for each chain. The chains must be in different tabs (the tools allow you to do this) so that different homology models can be built for each, and combined. The tools below are replaced with two tabs, for adding and selecting the target chains and for setting up the homology model for a selected chain. As for a homomultimer, the templates must be imported for each chain, and must have the required spatial arrangement to build the multimer.

  • Batch single template modeling—build a basic single-chain model for multiple sequences using a single template. This option is equivalent to the 1 target, 1 template option, but applied to multiple targets. A high similarity between each target and the template is required.

Get the target sequence step

Choose the sequence for which a homology model is built. When a sequence is chosen, its title is displayed to the right, and a green check mark appears to the left of the step name.

If the sequence is not already in the Multiple Sequence Viewer/Editor Panel (and set as Reference), click the Import Sequence link to import the sequence as a FASTA file (see Import Sequences for more information). The imported sequence is set as the Reference (moved to the first position in the sequence viewer). If multiple sequences are imported, the first is used as the target and set as reference. To change the target, right-click the intended sequence in the sequence viewer and choose Set as Reference from the menu. The target is marked in the sequence list with a green square to the left of the title.

Get 1st target step
Get other targets step

Choose the sequences for which the homology model is built, for batch single template modeling. You can import multiple sequences either into the sequence viewer tab, or when you choose the first target sequence (Get 1st target), or after you select the first sequence and the template (Get other targets). All of the sequences are marked as targets with a green square to the left of the title. If you import multiple sequences, for the next step you may need to set one of the targets as reference: this sequence is used in finding a template structure. The first imported sequence is set as the reference for finding a template. To set the reference to another sequence, right-click the intended sequence in the sequence viewer and choose Set as Reference from the menu.

Specify a template structure step
Specify template structures step
Find template chains step

Find or specify a template structure for building the model, or multiple template structures for chimeric modeling. When building a homomultimer, templates must be found for each chain. Building heteromultimers can be done with either a single or multiple templates for each chain, as chosen in the Set Up tab.

  • Click the Find link to run a BLAST search for the Reference sequence (See Homologs button) for more information. When the results are shown, select one or more structures to import, depending on the model type.

  • Click the Import link to import template structures. A file selector opens for locating and importing the files. You can select multiple files in the file selector to load as templates, either Maestro or PDB files. If you load multiple templates from Maestro files, all the structures in each file must be template structures. When you close the file selector, all of the structures you imported are selected as templates. If you add template structures subsequently, you will have to add the structures that are already imported to the selection.

  • If you need to use one or more homology models as templates, copy their sequences to the tab you are working in (if needed), and ensure that they are selected. This may be useful where it is necessary to generate intermediate models and then align them to produce a grafted model, for example with fusion proteins. By default, existing homology models are ignored as potential templates for further modeling.

The new sequences are marked in the list as templates, with a magenta color behind the structure icon. If multiple sequences are imported, just select the ones you want to use.

For batch single template modeling, the template structure is set as the reference, and the targets are listed below the template structure in the sequence viewer.

If you need to return to the search results, click the link again, and the BLAST, algorithm, opens.

Align sequences step

Align the sequences to the reference sequence, when a single template is in use.

If the template sequence was not previously aligned to the target, use the Run Alignment link to align them. The target must be set as the Reference (first sequence), except for batch single template modeling, when it is the template that must be set as the Reference. If there are sequences other than for the desired templates or targets in the sequence list in the current tab, select the desired sequences before the alignment is run. A Multiple Alignment is run, using the settings from the Align Pane.

The reported ID % indicates how well aligned the sequences are (overall). If the value is too low after alignment, the template may not be a good match with the target. Click Find Homologs to choose another template from the previous search results.

You can also try to improve the alignment at a critical region of the template by selecting the relevant residues and running the alignment again, or by manually editing the alignment.

For a 1 target 1 template model, you can improve the sequence alignment around the binding site by clicking the optimize button.

After selecting the ligand and the radius around the ligand that defines the binding site in the Optimize Sequence Alignment at Binding Site Dialog Box, click Optimize. The optimization moves gaps in both the target and template sequence away from (template) secondary structure elements in the binding site region, which should improve the built model in this region.

Align structures and sequences step

Align the structures in the templates to each other, and align the sequences to the reference sequence, for chimeric and consensus models. If there are sequences other than for the desired templates in the sequence list in the current tab, select the desired sequences before the alignment is run.

Click the Align Structures link to align the template structures. The first of the specified templates is used as the reference. To align on a different structure, reorder the template sequences in the sequence viewer, being careful to restore the previous selection or clear all selection before aligning. The alignment is only done for the sequences with a magenta background to their structure icons.

After the structures are aligned, click the Align Sequences link to align all the template sequences to the target sequence. The target must be set as the Reference (first sequence). A Multiple Alignment is run, using the settings from the Align Pane.

Define regions on templates step

For chimeric modeling, the regions on each template to use for the model must be defined. The second sequence is the default template (so it should have a structure).

Click the Pick button to define the regions of each template to be used in the model. By default, only the first template isused. It is highlighted in orange across the full width of the target (except for structureless residues, which show a cross-hatch pattern). To use a different template for a particular region of the model, press and drag along the portion of the desired sequence that you want to use. The highlight moves to this portion, and the panel reports that alternate regions have been defined. To change templates for a specific region, just press and drag along a different template. To start over with the default template, click the Reset link on the banner at the top of the tab.

When you are done picking alternate regions, close the banner or click the Pick button again to terminate picking regions. The orange highlights remain. To modify the regions, click Pick again.

Include ligands & cofactors step

By default, all recognized ligands from the template (or near the selected regions of the templates, for a chimeric model) are kept when the model is built. The number of ligands to be preserved (if greater than zero) is displayed above the Choose link.

To discard all ligands, cofactors, and waters, click the blue check mark to turn the option off. The icon turns gray, and the link is disabled. None of the extra molecules are kept.

To choose specific ligands to keep, or to keep cofactors or waters, or to set proximity constraints to ligands, click the link and follow the instructions in the Choose Ligands and Cofactors Dialog Box.

Change model settings step

Change settings for building the model. Click the link or the gear icon to change the modeling method, number of models, or other modeling and output options. The text under this step reflects the current settings.

The Knowledge-based method is the default. It constructs insertions and closes gaps using segments from known structures. This option supports multiple models of the structure. You can generate multiple models if there are insertions and deletions in the alignment. If there are no insertions or deletions, only one model will be generated, regardless of the number requested.

The Energy-based method uses energy calculations to construct and refine missing residues. It is much slower and only generates a single model, but it is also the only method that can be used with binding site proximity constraints. Side chains are optimized by default.

See Surface Generalized Born, SGB, continuum solvation model, homology model quality for more information on the process.

Generate Model button

Generate the homology model.

Create Tabs tab

For a heteromultimer model, create tabs in the sequence viewer for each sequence of the multimer. This tab has two steps, plus the Change model settings step.

Distribute target chains across tabs step

Distribute the target chains from the current tab over multiple tabs. This is useful if the sequence for the entire heteromultimer is in one tab. Select a sequence and optionally a template in the sequence viewer list, and click Copy Selected to create a new tab with this sequence. Alternatively, select all sequences and click Copy Selected to create a new tab for each sequence. If the sequences each have a single template directly below the sequence, you can select the sequences and the templates, and click Copy Selected to create a new tab for each sequence/template pair.

Select tabs to be used in model step

Select the tabs to be used in the model. The table includes all the View tabs in the sequence viewer. The columns show the tab name, the reference sequence name, and a settings button that switches to the Set Up tab for the selected view. Click Clear All to deselect all rows, Select All to select all rows. The settings icon is orange if the view has not been set up. You must perform the setup for all the views before you can generate the homology model of the heteromultimer.

Set Up tab

Set up the homology model for the heteromultimer chain that is selected in the Create Tabs tab . The steps are the same as above. The type of homology model used for the chain can be selected from the View N uses option menu, which has the 1 target, 1 template and Multiple templates (chimera) items from the Use menu.

Job toolbar

Manage job submission and settings. See Job Toolbar for a description of this toolbar.

Tutorials

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