Insights into Comparative Modeling of VHH Domains
Abstract
:1. Introduction
2. Results
2.1. Selection of VHH Sequences
2.2. Global Assessment of Structural Models
2.2.1. VHH Models
2.2.2. Difficult Cases
2.2.3. Impact of Sequence Similarity between Template and Query on Selected Models
2.3. Assessment of Structural Models in FRs and CDRs
2.4. Conservation of CDR Loop Termini Distances in Best Models in Comparison to Crystal Structures
2.5. Case Studies: Analyzing Local Backbone Conformations of Two VHH Domains in Different Scenarios for Two Representative Modeling Case Studies of VHH
2.5.1. Case 1
2.5.2. Case 2
2.5.3. Assessment of Backbone Conformational Sampling in Models Using Protein Blocks
2.6. Systematic Modeling of VHH Domains (Scenario 4—All)
3. Discussion
4. Materials and Methods
4.1. Dataset
4.2. Sequence Alignment
4.3. Structural Similarity of Protein Structures and Structural Models
4.4. Comparative Modeling of VHH
- In the first scenario, sequence identity between the query and template sequences is used as a criterion to select a template that shares the best sequence identity with each query sequence (namely scenario bestSeqIdTemp). It is the most classical protocol for template selection used in homology modeling,
- In the second scenario, templates are selected using structural similarity (to already solved structures of query sequences) measured using RMSD as criterion (namely scenario bestStructTemp). The template that had the lowest RMSD with the experimentally resolved structure of the query was chosen. This scenario is not possible in factual sense and it is a theoretical assessment, to check the maximal accuracy reachable with the closest structural template.
- The third scenario is based on a multi-template strategy. Three templates exhibiting the highest sequence identity with the query were selected (namely scenario 3bestSeqIdTemp). In a multiple template mode, better models are expected thanks to the combination of different structures.
- The last scenario is also a theoretical case to access the maximal reachable accuracy using all possible templates (namely scenario All). Indeed, all previous scenarios had a specific a priori. Here, all structures were used independently as potential templates. It permits us to have more insights that would have been missed in previous scenarios such as; could another VHH template, other than the best sequence identity, and the best structurally close ones provide a better structural model.
4.5. Local Conformational Analysis
4.6. Protein Structure and Structural Model Visualization
4.7. Scripting
Supplementary Materials
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Conflicts of Interest
Appendix A
Prosa II Z Scores for 22 Difficult Cases | ||||
---|---|---|---|---|
SC1 | SC2 | SC3 | Crystal Structure | |
1I3U:A | −4.98 | −5.37 | −5.36 | −5.53 |
1KXV:D | −4.08 | −6.4 | −4.41 | −4.73 |
2X1O:B | −6.06 | −5.64 | −5.68 | −5.72 |
2X6M:A | −6.01 | −5.98 | −5.8 | −6.84 |
3EAK:B | −5.45 | −5.63 | −5.81 | −5.97 |
3G9A:B | −4.51 | −4.75 | −4.14 | −5.79 |
3K3Q:A | −6.12 | −5.87 | −5.89 | −5.22 |
3K81:B | −4.91 | −5.11 | −5.21 | −5.44 |
3SN6:N | −4.02 | −4.05 | −5.21 | −5.14 |
4C57:C | −5.54 | −5.02 | −5.00 | −5.80 |
4EIZ:D | −6.94 | −6.01 | −6.05 | −6.56 |
4GRW:F | −5.76 | −5.78 | −6.52 | −6.6 |
4HEP:G | −5.48 | −6.19 | −5.98 | −6.59 |
4IDL:A | −4.40 | −4.25 | −5.18 | −4.30 |
4LAJ:H | −5.94 | −5.84 | −6.45 | −6.72 |
4WEN:B | −4.93 | −6.09 | −6.15 | −6.4 |
4WGV:D | −4.95 | −4.78 | −5.21 | −5.04 |
5BOP:C | −5.97 | −6.09 | −6.12 | −6.04 |
5E7B:A | −5.58 | −6.12 | −5.99 | −6.16 |
5F1O:B | −5.77 | −6.42 | −6.59 | −6.71 |
5F7L:B | −6.43 | −5.78 | −5.57 | −5.66 |
5GXB:B | −6 | −6.15 | −5.75 | −5.35 |
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Query | RMSD SC1 (Å) | RMSD SC2 (Å) | RMSD SC3 (Å) | SI SC1 (%) | SI SC2 (%) | MSI SC3 (%) | RMSD T SC1 (Å) | RMSD T SC2 (Å) |
---|---|---|---|---|---|---|---|---|
3G9A:B | 7.87 | 3.46 * | 3.89 | 69.17 | 59.63 | 68.2 | 4.63 | 1.82 |
3SN6:N | 6.87 | 6.87 | 3.05 * | 83.03 | 83.03 | 78.7 | 1.42 | 1.42 |
3EAK:B | 5.59 | 1.39 * | 1.64 | 67.86 | 66.39 | 67.2 | 1.89 | 1.44 |
5E7B:A | 5.52 | 4.01 * | 6.21 | 75.63 | 70.53 | 74.1 | 4.04 | 1.56 |
4C57:C | 5.49 | 1.78 * | 4.13 | 67.86 | 54.1 | 67.0 | 2.13 | 1.74 |
4IDL:A | 5.13 | 2.72 * | 3.18 | 67.26 | 60.17 | 65.9 | 3.01 | 1.27 |
5F1O:B | 4.28 | 6.62 | 2.09 * | 76.47 | 68.75 | 74.4 | 3.91 | 1.08 |
1KXV:D | 4.08 | 2.00 * | 4.47 | 64.96 | 63.33 | 64.1 | 2.89 | 2.00 |
5GXB:B | 3.94 | 1.74 * | 4.01 | 78.13 | 69.04 | 77.3 | 3.21 | 1.43 |
5BOP:C | 3.91 | 1.36 * | 1.97 | 78.63 | 70.24 | 78.0 | 2.46 | 1.14 |
4HEP:G | 3.81 | 5.09 | 3.60 * | 77.23 | 63.47 | 75.1 | 3.06 | 1.84 |
5F7L:B | 3.29 | 1.34 * | 2.66 | 76.72 | 71.42 | 75.5 | 1.90 | 1.01 |
4WEN:B | 3.28 | 0.99 | 0.68 * | 75.63 | 74.38 | 74.7 | 3.23 | 0.97 |
4WGV:D | 3.04 | 2.49 * | 2.94 | 75.83 | 64.34 | 74.9 | 2.86 | 1.73 |
4EIZ:D | 2.93 | 6.89 | 2.37 * | 76.78 | 73.21 | 76.3 | 3.14 | 1.12 |
3K3Q:A | 2.86 | 5.96 | 2.55 * | 56.19 | 50.00 | 55.1 | 2.03 | 1.71 |
2X1O:B | 2.57 | 4.73 | 2.53 * | 74.17 | 69.64 | 73.6 | 2.86 | 1.32 |
1I3U:A | 2.06 | 4.31 | 2.29 * | 65.85 | 61.46 | 64.7 | 1.66 | 1.53 |
4LAJ:H | 2.29 | 4.30 | 2.04 * | 79.67 | 65.21 | 78.6 | 2.11 | 1.60 |
2X6M:A | 2.51 | 3.94 | 1.60 * | 70.58 | 64.34 | 69.9 | 3.12 | 1.25 |
4GRW:F | 2.43 | 3.77 | 1.97 * | 79.67 | 71.42 | 76.8 | 2.11 | 1.54 |
3K81:B | 2.74 | 2.45 * | 3.41 | 72.50 | 65.81 | 71.5 | 2.80 | 1.91 |
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Vattekatte, A.M.; Cadet, F.; Gelly, J.-C.; de Brevern, A.G. Insights into Comparative Modeling of VHH Domains. Int. J. Mol. Sci. 2021, 22, 9771. https://doi.org/10.3390/ijms22189771
Vattekatte AM, Cadet F, Gelly J-C, de Brevern AG. Insights into Comparative Modeling of VHH Domains. International Journal of Molecular Sciences. 2021; 22(18):9771. https://doi.org/10.3390/ijms22189771
Chicago/Turabian StyleVattekatte, Akhila Melarkode, Frédéric Cadet, Jean-Christophe Gelly, and Alexandre G. de Brevern. 2021. "Insights into Comparative Modeling of VHH Domains" International Journal of Molecular Sciences 22, no. 18: 9771. https://doi.org/10.3390/ijms22189771