Membrane Environment Modulates Ligand-Binding Propensity of P2Y12 Receptor
The binding of natural ligands and synthetic drugs to the P2Y12 receptor is of great interest because of its crucial role in platelets activation and the therapy of arterial thrombosis. Up to now, all computational studies of P2Y12 concentrated on the available crystal structures, while the role of...
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| Format: | Article |
| Language: | English |
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MDPI AG
2021-04-01
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| Series: | Pharmaceutics |
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| Online Access: | https://www.mdpi.com/1999-4923/13/4/524 |
| _version_ | 1797538221743144960 |
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| author | Fatemeh Haghighi Semen Yesylevskyy Siamak Davani Christophe Ramseyer |
| author_facet | Fatemeh Haghighi Semen Yesylevskyy Siamak Davani Christophe Ramseyer |
| author_sort | Fatemeh Haghighi |
| collection | DOAJ |
| description | The binding of natural ligands and synthetic drugs to the P2Y12 receptor is of great interest because of its crucial role in platelets activation and the therapy of arterial thrombosis. Up to now, all computational studies of P2Y12 concentrated on the available crystal structures, while the role of intrinsic protein dynamics and the membrane environment in the functioning of P2Y12 was not clear. In this work, we performed all-atom molecular dynamics simulations of the full-length P2Y<sub>12</sub> receptor in three different membrane environments and in two possible conformations derived from available crystal structures. The binding of ticagrelor, its two major metabolites, adenosine diphosphate (ADP) and 2-Methylthioadenosine diphosphate (2MeS-ADP) as agonist, and ethyl 6-[4-(benzylsulfonylcarbamoyl)piperidin-1-yl]-5-cyano-2-methylpyridine-3-carboxylate (AZD1283)as antagonist were assessed systematically by means of ensemble docking. It is shown that the binding of all ligands becomes systematically stronger with the increase of the membrane rigidity. Binding of all ligands to the agonist-bound-like conformations is systematically stronger in comparison to antagonist-bound-likes ones. This is dramatically opposite to the results obtained for static crystal structures. Our results show that accounting for internal protein dynamics, strongly modulated by its lipid environment, is crucial for correct assessment of the ligand binding to P2Y12. |
| first_indexed | 2024-03-10T12:27:27Z |
| format | Article |
| id | doaj.art-d9e4008cb9cf41ec96d6c1af6e2ecd61 |
| institution | Directory Open Access Journal |
| issn | 1999-4923 |
| language | English |
| last_indexed | 2024-03-10T12:27:27Z |
| publishDate | 2021-04-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Pharmaceutics |
| spelling | doaj.art-d9e4008cb9cf41ec96d6c1af6e2ecd612023-11-21T14:55:45ZengMDPI AGPharmaceutics1999-49232021-04-0113452410.3390/pharmaceutics13040524Membrane Environment Modulates Ligand-Binding Propensity of P2Y12 ReceptorFatemeh Haghighi0Semen Yesylevskyy1Siamak Davani2Christophe Ramseyer3Laboratoire Chrono Environnement UMR CNRS 6249, Université de Bourgogne Franche-Comté, 16 route de Gray, CEDEX, 25030 Besançon, FranceLaboratoire Chrono Environnement UMR CNRS 6249, Université de Bourgogne Franche-Comté, 16 route de Gray, CEDEX, 25030 Besançon, FranceUnité de Recherche EA 3920, Université de Bourgogne Franche-Comté, 19 rue Ambroise Paré, CEDEX, 25000 Besançon, FranceLaboratoire Chrono Environnement UMR CNRS 6249, Université de Bourgogne Franche-Comté, 16 route de Gray, CEDEX, 25030 Besançon, FranceThe binding of natural ligands and synthetic drugs to the P2Y12 receptor is of great interest because of its crucial role in platelets activation and the therapy of arterial thrombosis. Up to now, all computational studies of P2Y12 concentrated on the available crystal structures, while the role of intrinsic protein dynamics and the membrane environment in the functioning of P2Y12 was not clear. In this work, we performed all-atom molecular dynamics simulations of the full-length P2Y<sub>12</sub> receptor in three different membrane environments and in two possible conformations derived from available crystal structures. The binding of ticagrelor, its two major metabolites, adenosine diphosphate (ADP) and 2-Methylthioadenosine diphosphate (2MeS-ADP) as agonist, and ethyl 6-[4-(benzylsulfonylcarbamoyl)piperidin-1-yl]-5-cyano-2-methylpyridine-3-carboxylate (AZD1283)as antagonist were assessed systematically by means of ensemble docking. It is shown that the binding of all ligands becomes systematically stronger with the increase of the membrane rigidity. Binding of all ligands to the agonist-bound-like conformations is systematically stronger in comparison to antagonist-bound-likes ones. This is dramatically opposite to the results obtained for static crystal structures. Our results show that accounting for internal protein dynamics, strongly modulated by its lipid environment, is crucial for correct assessment of the ligand binding to P2Y12.https://www.mdpi.com/1999-4923/13/4/524ticagrelorP2Y<sub>12</sub> receptorsplateletsmolecular dynamics |
| spellingShingle | Fatemeh Haghighi Semen Yesylevskyy Siamak Davani Christophe Ramseyer Membrane Environment Modulates Ligand-Binding Propensity of P2Y12 Receptor Pharmaceutics ticagrelor P2Y<sub>12</sub> receptors platelets molecular dynamics |
| title | Membrane Environment Modulates Ligand-Binding Propensity of P2Y12 Receptor |
| title_full | Membrane Environment Modulates Ligand-Binding Propensity of P2Y12 Receptor |
| title_fullStr | Membrane Environment Modulates Ligand-Binding Propensity of P2Y12 Receptor |
| title_full_unstemmed | Membrane Environment Modulates Ligand-Binding Propensity of P2Y12 Receptor |
| title_short | Membrane Environment Modulates Ligand-Binding Propensity of P2Y12 Receptor |
| title_sort | membrane environment modulates ligand binding propensity of p2y12 receptor |
| topic | ticagrelor P2Y<sub>12</sub> receptors platelets molecular dynamics |
| url | https://www.mdpi.com/1999-4923/13/4/524 |
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