Analysis of AlphaFold and molecular dynamics structure predictions of mutations in serpins

• Published in: PloS one Vol. 19; no. 7; p. e0304451
• Main Authors: Garrido-Rodríguez, Pedro, Carmena-Bargueño, Miguel, de la Morena-Barrio, María Eugenia, Bravo-Pérez, Carlos, de la Morena-Barrio, Belén, Cifuentes-Riquelme, Rosa, Lozano, María Luisa, Pérez-Sánchez, Horacio, Corral, Javier
• Format: Journal Article
• Language: English
• Published: United States Public Library of Science 05.07.2024; Public Library of Science (PLoS)
• Subjects: Anticoagulants; Antithrombin; Antithrombin III - chemistry; Antithrombin III - genetics; Antithrombin III - metabolism; Artificial intelligence; Biology and Life Sciences; Conformation; Crystal defects; Crystallography; Dynamic structural analysis; Genetic aspects; Humans; Molecular dynamics; Molecular Dynamics Simulation; Molecular structure; Mutation; Physical Sciences; Plasma; Predictions; Protease inhibitors; Protein Conformation; Protein Folding; Proteinase inhibitors; Proteins; Serine proteinase inhibitors; Serpins - chemistry; Serpins - genetics; Serpins - metabolism; Simulation; Thrombin; Thrombophilia; Thrombosis; New York
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0304451

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.