Canavan Disease: Task 05 - Homology Modelling
Contents
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% | |
</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>).
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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>).
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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>).
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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>).
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iTasser
iTasser continues to show the trend that is already observable if looking at the results of Modeller and Swissmodel. Taking a look at the models produced out of the high sequence similarity templates, it is visible that iTasser creates accurate models for the target sequence (see <xr id="2O53_it">Figure</xr> and <xr id="2GU2_it">Figure</xr>). However if the visualization in pymol is compared to the result Modleler and Swissmodel created iTasser seems to be a little less precise. The spacial orientation of the secondary structure elements seem a bit off compared to the models created by the two other methods.
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Looking at the calculated models based on 2QJ8 and 1YW4, iTasser definitely produces much worse results than Modeller and Swissmodel. Comparing target and template structures, concerning the positions of the atoms, the model seems to fall in between the two structures leaning more towards the template structure (compare to <xr id="2O53_it">Figure</xr> and <xr id="2GU2_it">Figure</xr>).
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Therefore the conclusion out of the examination of the structures via Pymol, should be that Modeller's overall performance is exceptional, only being beaten by Swissmodel for templates with a high sequence similarity. iTasser however is performing worse in every example additionally to the fact that the computing time is much longer if compared to the other methods.
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 | |
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As it can be seen in the <xr id="model">Table</xr> xxxxx.
Tasks
- Link to Task 01: Canavan Disease
- Link to Task 02: Alignments
- Link to Task 03: Sequence-based Predictions
- Link to Task 04: Structural Alignments
- Link to Task 05: Homology Modelling
- Link to Task 06: Protein Structure Prediction from Evolutionary Sequence Variation
- Link to Task 07: Researching SNPs
- Link to Task 08: Sequence-based Mutation Analysis
- Link to Task 09: Structure-based Mutation Analysis
- Link to Task 10: Normal Mode Analysis
- Link to Task 11: Molecular Dynamics Simulation
