The Interaction of Factor Xa and IXa with Non-Activated Antithrombin in Michaelis Complex: Insights from Enhanced-Sampling Molecular Dynamics Simulations
The interaction between coagulation factors Xa and IXa and the activated state of their inhibitor, antithrombin (AT),have been investigated using X-ray diffraction studies. However, only mutagenesis data are available for non-activated AT. Our aim was to propose a model based on docking and advanced...
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| Format: | Article |
| Language: | English |
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MDPI AG
2023-05-01
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| Series: | Biomolecules |
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| Online Access: | https://www.mdpi.com/2218-273X/13/5/795 |
| _version_ | 1797600892082454528 |
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| author | Gábor Balogh Zsuzsanna Bereczky |
| author_facet | Gábor Balogh Zsuzsanna Bereczky |
| author_sort | Gábor Balogh |
| collection | DOAJ |
| description | The interaction between coagulation factors Xa and IXa and the activated state of their inhibitor, antithrombin (AT),have been investigated using X-ray diffraction studies. However, only mutagenesis data are available for non-activated AT. Our aim was to propose a model based on docking and advanced-sampling molecular dynamics simulations that can reveal the conformational behavior of the systems when AT is not binding a pentasaccharide. We built the initial structure for non-activated AT-FXa and AT-FIXa complexes using HADDOCK 2.4. The conformational behavior was studied using Gaussian accelerated molecular dynamics simulations. In addition to the docked complexes, two systems based on the X-ray structures were also simulated, with and without the ligand. The simulations revealed large variability in conformation for both factors. In the docking-based complex of AT-FIXa, conformations with stable Arg150–AT interactions can exist for longer time periods but the system also has a higher tendency for reaching states with very limited interaction with the “exosite” of AT. By comparing simulations with or without the pentasaccharide, we were able to gain insights into the effects of conformational activation on the Michaelis complexes. RMSF analysis and correlation calculations for the alpha-carbon atoms revealed important details of the allosteric mechanisms. Our simulations provide atomistic models for better understanding the conformational activation mechanism of AT against its target factors. |
| first_indexed | 2024-03-11T03:55:17Z |
| format | Article |
| id | doaj.art-f1741b5f786f41e1b58f1f8b769fa0a3 |
| institution | Directory Open Access Journal |
| issn | 2218-273X |
| language | English |
| last_indexed | 2024-03-11T03:55:17Z |
| publishDate | 2023-05-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Biomolecules |
| spelling | doaj.art-f1741b5f786f41e1b58f1f8b769fa0a32023-11-18T00:39:18ZengMDPI AGBiomolecules2218-273X2023-05-0113579510.3390/biom13050795The Interaction of Factor Xa and IXa with Non-Activated Antithrombin in Michaelis Complex: Insights from Enhanced-Sampling Molecular Dynamics SimulationsGábor Balogh0Zsuzsanna Bereczky1Division of Clinical Laboratory Science, Department of Laboratory Medicine, Faculty of Medicine, University of Debrecen, 4032 Debrecen, HungaryDivision of Clinical Laboratory Science, Department of Laboratory Medicine, Faculty of Medicine, University of Debrecen, 4032 Debrecen, HungaryThe interaction between coagulation factors Xa and IXa and the activated state of their inhibitor, antithrombin (AT),have been investigated using X-ray diffraction studies. However, only mutagenesis data are available for non-activated AT. Our aim was to propose a model based on docking and advanced-sampling molecular dynamics simulations that can reveal the conformational behavior of the systems when AT is not binding a pentasaccharide. We built the initial structure for non-activated AT-FXa and AT-FIXa complexes using HADDOCK 2.4. The conformational behavior was studied using Gaussian accelerated molecular dynamics simulations. In addition to the docked complexes, two systems based on the X-ray structures were also simulated, with and without the ligand. The simulations revealed large variability in conformation for both factors. In the docking-based complex of AT-FIXa, conformations with stable Arg150–AT interactions can exist for longer time periods but the system also has a higher tendency for reaching states with very limited interaction with the “exosite” of AT. By comparing simulations with or without the pentasaccharide, we were able to gain insights into the effects of conformational activation on the Michaelis complexes. RMSF analysis and correlation calculations for the alpha-carbon atoms revealed important details of the allosteric mechanisms. Our simulations provide atomistic models for better understanding the conformational activation mechanism of AT against its target factors.https://www.mdpi.com/2218-273X/13/5/795antithrombincoagulation factor Xcoagulation factor IXprotein–protein interactionprotein dockingmolecular dynamics |
| spellingShingle | Gábor Balogh Zsuzsanna Bereczky The Interaction of Factor Xa and IXa with Non-Activated Antithrombin in Michaelis Complex: Insights from Enhanced-Sampling Molecular Dynamics Simulations Biomolecules antithrombin coagulation factor X coagulation factor IX protein–protein interaction protein docking molecular dynamics |
| title | The Interaction of Factor Xa and IXa with Non-Activated Antithrombin in Michaelis Complex: Insights from Enhanced-Sampling Molecular Dynamics Simulations |
| title_full | The Interaction of Factor Xa and IXa with Non-Activated Antithrombin in Michaelis Complex: Insights from Enhanced-Sampling Molecular Dynamics Simulations |
| title_fullStr | The Interaction of Factor Xa and IXa with Non-Activated Antithrombin in Michaelis Complex: Insights from Enhanced-Sampling Molecular Dynamics Simulations |
| title_full_unstemmed | The Interaction of Factor Xa and IXa with Non-Activated Antithrombin in Michaelis Complex: Insights from Enhanced-Sampling Molecular Dynamics Simulations |
| title_short | The Interaction of Factor Xa and IXa with Non-Activated Antithrombin in Michaelis Complex: Insights from Enhanced-Sampling Molecular Dynamics Simulations |
| title_sort | interaction of factor xa and ixa with non activated antithrombin in michaelis complex insights from enhanced sampling molecular dynamics simulations |
| topic | antithrombin coagulation factor X coagulation factor IX protein–protein interaction protein docking molecular dynamics |
| url | https://www.mdpi.com/2218-273X/13/5/795 |
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