Canavan Disease: Task 05 - Homology Modelling

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LabJournal

Dataset

The models are calculated with three different modellers: Modeller, SwissModel and iTasser. To compare the modellers two sequences per sequence similarity set were chosen:

<figtable id="dataset">

Dataset composition
PDB-id Description Criterium
2O4H ASPA from Human with bound N-phosphonomethyl-L-aspartate reference structure
2O53 Crystal structure of apo-Aspartoacylase from human brain sequence identity 100%
2GU2 ASPA from Rat sequence identity 84%
2QJ8 ASPA family protein from mesorhizobium loti sequence identity 16%
1YW4 Succinylglutamate Desuccinylase from "Chromobacterium violaceum" sequence identity 14%
Overview of the dataset composition for Task 05, containing a brief description of the the chosen structures and the sequence identity to the reference ACY2 protein

</figtable>

Model creation

Each modelling algorithm was used to produce models for 2HO4 based on four different template proteins. Those models can be examined in the following section except the model that Swissmodel should have created based in 1YW4, as Swissmodel was not able to perform this task.

Modeller

Modeller produced extremely accurate models for the target protein given templates with a high sequence similarity. Both 2O53 and 2GU2 are already highly similar in structure if visually compared to 2O4H. Performing a structural alignment of the template structures to 2O4H result in RMDS below 1Å. Therefore it is to be expected that the models generated should be very accurate, and this is exactly what can be observed (see <xr id="2O53_md">Figure</xr> and <xr id="2GU2_md">Figure</xr>).

</figure>

</figure>

<figure id="2O53_md">

Representation of the target (2O4H), the template (2O53) and the generated model in pymol. 2O4H is displayed in orange including the bound zinc atom and compound at the active site of ASPA. The template used to generate the model is displayed in green. The produced model is displayed in blue.

<figure id="2GU2_md">

Representation of the target (2O4H), the template (2GU2) and the generated model in pymol. 2O4H is displayed in orange including the bound zinc atom and compound at the active site of ASPA. The template used to generate the model is displayed in green. The produced model is displayed in blue.

Taking a look ate the model generated for 2O4H with the aid of 2QJ8 and 1WY4 as template which have both a sequence similarity below 20%, the results are sill very good. There are visible differences between the target and the models like larger loop regions or secondary structure elements with conformations that are slightly miss predicted. However if the aligned target and models are compared to their original template there is a big difference detectable (compare <xr id="2QJ8_md">Figure</xr> and <xr id="1YW4_md">Figure</xr>).

</figure>

</figure>

<figure id="2QJ8_md">

Representation of the target (2O4H), the template (2QJ8) and the generated model in pymol. 2O4H is displayed in orange including the bound zinc atom and compound at the active site of ASPA. The template used to generate the model is displayed in green. The produced model is displayed in blue.

<figure id="1YW4_md">

Representation of the target (2O4H), the template (1YW4) and the generated model in pymol. 2O4H is displayed in orange including the bound zinc atom and compound at the active site of ASPA. The template used to generate the model is displayed in green. The produced model is displayed in blue.

Swissmodel

Examining the models created by Swissmodel with high sequence similarity templates in Pymol together with the templates and target, reveals that Swissmodel creates very accurate models as well. One visible difference compared the models created by Modeller is that Swissmodel seems to created the model for the length of the target opposed to Modeller where for example the N and C-terminus of the polypeptide is well extended over the length of the actual target (see <xr id="2O53_sm">Figure</xr> and <xr id="2GU2_sm">Figure</xr>).

</figure>

</figure>

<figure id="2O53_sm">

Representation of the target (2O4H), the template (2O53) and the generated model in pymol. 2O4H is displayed in orange including the bound zinc atom and compound at the active site of ASPA. The template used to generate the model is displayed in green. The produced model is displayed in blue.

<figure id="2GU2_sm">

Representation of the target (2O4H), the template (2GU2) and the generated model in pymol. 2O4H is displayed in orange including the bound zinc atom and compound at the active site of ASPA. The template used to generate the model is displayed in green. The produced model is displayed in blue.

Regarding the models created from templates with a sequence similarity of less than 30% to 2O4H, the remark that Swissmodel was not able to form a model with 1YW4 as template has to be made. The modeling process with 2QJ8 as template has been successful however. Taking a closer look at the model created from 2QJ8 is get visible that Swissmodel at least for this specific example does not perform was well as Modeller using a template with low sequence similarity. The overall positioning of the atoms is correct, but the prediction of secondary structure elements is much worse. Some residues do not even have a predicted spacial position (see <xr id="2QJ8_sm">Figure</xr>).

<figure id="2QJ8_sm">

Representation of the target (2O4H), the template (2QJ8) and the generated model in pymol. 2O4H is displayed in orange including the bound zinc atom and compound at the active site of ASPA. The template used to generate the model is displayed in green. The produced model is displayed in blue.

</figure>

iTasser

</figure>

</figure>

<figure id="2O53_it">

<figure id="2GU2_it">


</figure>

</figure>

<figure id="2QJ8_it">

<figure id="1YW4_it">

Model evaluation

<figtable id="model">

Comparison of Multiple Sequence Alignment Tools
Modeller SwissModel iTasser
2O53 2GU2 2QJ8 1YW4 2O53 2GU2 2QJ8 2O53 2GU2 2QJ8 1YW4
GDT Score 9.023 11.093 6.954 8.113 99.669 54.470 11.589 9.272 10.513 7.368 9.520
C_alpha RMSD 0.1Å 0.2Å 17.5Å 0.2Å 0.1Å 0.1Å 7.5Å 8.0Å 7.1Å 15.5Å 2.2Å
Correlation x x x x x x x x x x x
text

</figtable>

As it can be seen in the <xr id="model">Table</xr> xxxxx.

Tasks

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