Conservation of binding properties in protein models
We study the models submitted to round 12 of the Critical Assessment of protein Structure Prediction (CASP) experiment to assess how well the binding properties are conserved when the X-ray structures of the target proteins are replaced by their models. To explore small molecule binding we generate...
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| Format: | Article |
| Language: | English |
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Elsevier
2021-01-01
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| Series: | Computational and Structural Biotechnology Journal |
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| Online Access: | http://www.sciencedirect.com/science/article/pii/S2001037021001604 |
| _version_ | 1818871707889303552 |
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| author | Megan Egbert Kathryn A. Porter Usman Ghani Sergei Kotelnikov Thu Nguyen Ryota Ashizawa Dima Kozakov Sandor Vajda |
| author_facet | Megan Egbert Kathryn A. Porter Usman Ghani Sergei Kotelnikov Thu Nguyen Ryota Ashizawa Dima Kozakov Sandor Vajda |
| author_sort | Megan Egbert |
| collection | DOAJ |
| description | We study the models submitted to round 12 of the Critical Assessment of protein Structure Prediction (CASP) experiment to assess how well the binding properties are conserved when the X-ray structures of the target proteins are replaced by their models. To explore small molecule binding we generate distributions of molecular probes – which are fragment-sized organic molecules of varying size, shape, and polarity – around the protein, and count the number of interactions between each residue and the probes, resulting in a vector of interactions we call a binding fingerprint. The similarity between two fingerprints, one for the X-ray structure and the other for a model of the protein, is determined by calculating the correlation coefficient between the two vectors. The resulting correlation coefficients are shown to correlate with global measures of accuracy established in CASP, and the relationship yields an accuracy threshold that has to be reached for meaningful binding surface conservation. The clusters formed by the probe molecules reliably predict binding hot spots and ligand binding sites in both X-ray structures and reasonably accurate models of the target, but ensembles of models may be needed for assessing the availability of proper binding pockets. We explored ligand docking to the few targets that had bound ligands in the X-ray structure. More targets were available to assess the ability of the models to reproduce protein–protein interactions by docking both the X-ray structures and models to their interaction partners in complexes. It was shown that this application is more difficult than finding small ligand binding sites, and the success rates heavily depend on the local structure in the potential interface. In particular, predicted conformations of flexible loops are frequently incorrect in otherwise highly accurate models, and may prevent predicting correct protein–protein interactions. |
| first_indexed | 2024-12-19T12:27:12Z |
| format | Article |
| id | doaj.art-fb570d50938e430d9a58d13c5c7cd359 |
| institution | Directory Open Access Journal |
| issn | 2001-0370 |
| language | English |
| last_indexed | 2024-12-19T12:27:12Z |
| publishDate | 2021-01-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Computational and Structural Biotechnology Journal |
| spelling | doaj.art-fb570d50938e430d9a58d13c5c7cd3592022-12-21T20:21:33ZengElsevierComputational and Structural Biotechnology Journal2001-03702021-01-011925492566Conservation of binding properties in protein modelsMegan Egbert0Kathryn A. Porter1Usman Ghani2Sergei Kotelnikov3Thu Nguyen4Ryota Ashizawa5Dima Kozakov6Sandor Vajda7Department of Biomedical Engineering, Boston University, Boston, MA 02215, United StatesDepartment of Biomedical Engineering, Boston University, Boston, MA 02215, United StatesDepartment of Biomedical Engineering, Boston University, Boston, MA 02215, United StatesDepartment of Applied Mathematics and Statistics, Stony Brook University, Stony Brook, NY 11794, United States; Laufer Center for Physical and Quantitative Biology, Stony Brook University, Stony Brook, NY 11794, United StatesLaufer Center for Physical and Quantitative Biology, Stony Brook University, Stony Brook, NY 11794, United StatesDepartment of Applied Mathematics and Statistics, Stony Brook University, Stony Brook, NY 11794, United States; Laufer Center for Physical and Quantitative Biology, Stony Brook University, Stony Brook, NY 11794, United StatesDepartment of Applied Mathematics and Statistics, Stony Brook University, Stony Brook, NY 11794, United States; Laufer Center for Physical and Quantitative Biology, Stony Brook University, Stony Brook, NY 11794, United StatesDepartment of Biomedical Engineering, Boston University, Boston, MA 02215, United States; Department of Chemistry, Boston University, Boston, MA 02215, United States; Corresponding author at: Department of Biomedical Engineering, Boston University, 44 Cummington Mall, Boston, MA 02215, United States.We study the models submitted to round 12 of the Critical Assessment of protein Structure Prediction (CASP) experiment to assess how well the binding properties are conserved when the X-ray structures of the target proteins are replaced by their models. To explore small molecule binding we generate distributions of molecular probes – which are fragment-sized organic molecules of varying size, shape, and polarity – around the protein, and count the number of interactions between each residue and the probes, resulting in a vector of interactions we call a binding fingerprint. The similarity between two fingerprints, one for the X-ray structure and the other for a model of the protein, is determined by calculating the correlation coefficient between the two vectors. The resulting correlation coefficients are shown to correlate with global measures of accuracy established in CASP, and the relationship yields an accuracy threshold that has to be reached for meaningful binding surface conservation. The clusters formed by the probe molecules reliably predict binding hot spots and ligand binding sites in both X-ray structures and reasonably accurate models of the target, but ensembles of models may be needed for assessing the availability of proper binding pockets. We explored ligand docking to the few targets that had bound ligands in the X-ray structure. More targets were available to assess the ability of the models to reproduce protein–protein interactions by docking both the X-ray structures and models to their interaction partners in complexes. It was shown that this application is more difficult than finding small ligand binding sites, and the success rates heavily depend on the local structure in the potential interface. In particular, predicted conformations of flexible loops are frequently incorrect in otherwise highly accurate models, and may prevent predicting correct protein–protein interactions.http://www.sciencedirect.com/science/article/pii/S2001037021001604Structure predictionProtein binding siteProtein–protein interactionQuality measuresBinding hot spotsProtein mapping |
| spellingShingle | Megan Egbert Kathryn A. Porter Usman Ghani Sergei Kotelnikov Thu Nguyen Ryota Ashizawa Dima Kozakov Sandor Vajda Conservation of binding properties in protein models Computational and Structural Biotechnology Journal Structure prediction Protein binding site Protein–protein interaction Quality measures Binding hot spots Protein mapping |
| title | Conservation of binding properties in protein models |
| title_full | Conservation of binding properties in protein models |
| title_fullStr | Conservation of binding properties in protein models |
| title_full_unstemmed | Conservation of binding properties in protein models |
| title_short | Conservation of binding properties in protein models |
| title_sort | conservation of binding properties in protein models |
| topic | Structure prediction Protein binding site Protein–protein interaction Quality measures Binding hot spots Protein mapping |
| url | http://www.sciencedirect.com/science/article/pii/S2001037021001604 |
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