Academic Journal
Analysis of AlphaFold and molecular dynamics structure predictions of mutations in serpins.
| Title: | Analysis of AlphaFold and molecular dynamics structure predictions of mutations in serpins. |
|---|---|
| Authors: | Pedro Garrido-Rodríguez, Miguel Carmena-Bargueño, María Eugenia de la Morena-Barrio, Carlos Bravo-Pérez, Belén de la Morena-Barrio, Rosa Cifuentes-Riquelme, María Luisa Lozano, Horacio Pérez-Sánchez, Javier Corral |
| Source: | PLoS ONE, Vol 19, Iss 7, p e0304451 (2024) |
| Publisher Information: | Public Library of Science (PLoS), 2024. |
| Publication Year: | 2024 |
| Collection: | LCC:Medicine LCC:Science |
| Subject Terms: | Medicine, Science |
| More Details: | Serine protease inhibitors (serpins) include thousands of structurally conserved proteins playing key roles in many organisms. Mutations affecting serpins may disturb their conformation, leading to inactive forms. Unfortunately, conformational consequences of serpin mutations are difficult to predict. In this study, we integrate experimental data of patients with mutations affecting one serpin with the predictions obtained by AlphaFold and molecular dynamics. Five SERPINC1 mutations causing antithrombin deficiency, the strongest congenital thrombophilia were selected from a cohort of 350 unrelated patients based on functional, biochemical, and crystallographic evidence supporting a folding defect. AlphaFold gave an accurate prediction for the wild-type structure. However, it also produced native structures for all variants, regardless of complexity or conformational consequences in vivo. Similarly, molecular dynamics of up to 1000 ns at temperatures causing conformational transitions did not show significant changes in the native structure of wild-type and variants. In conclusion, AlphaFold and molecular dynamics force predictions into the native conformation at conditions with experimental evidence supporting a conformational change to other structures. It is necessary to improve predictive strategies for serpins that consider the conformational sensitivity of these molecules. |
| Document Type: | article |
| File Description: | electronic resource |
| Language: | English |
| ISSN: | 1932-6203 |
| Relation: | https://doaj.org/toc/1932-6203 |
| DOI: | 10.1371/journal.pone.0304451 |
| Access URL: | https://doaj.org/article/8c903214e7494b25930f3e8d5745ede3 |
| Accession Number: | edsdoj.8c903214e7494b25930f3e8d5745ede3 |
| Database: | Directory of Open Access Journals |
| Full text is not displayed to guests. | Login for full access. |
| ISSN: | 19326203 |
|---|---|
| DOI: | 10.1371/journal.pone.0304451 |
| Published in: | PLoS ONE |
| Language: | English |