Unsupervised Classification of G-Protein Coupled Receptors and Their Conformational States Using IChem Intramolecular Interaction Patterns
| Autor: | Franck Da Silva, Esther Kellenberger, Didier Rognan, Florian Koensgen |
|---|---|
| Přispěvatelé: | Laboratoire d'Innovation Thérapeutique (LIT), Centre National de la Recherche Scientifique (CNRS)-Université de Strasbourg (UNISTRA)-Institut de Chimie du CNRS (INC), Université de Strasbourg (UNISTRA)-Centre National de la Recherche Scientifique (CNRS) |
| Rok vydání: | 2019 |
| Předmět: |
MESH: Ions
Protein Conformation General Chemical Engineering MESH: Receptors G-Protein-Coupled Computational biology Molecular Dynamics Simulation Library and Information Sciences Receptors G-Protein-Coupled 03 medical and health sciences Molecular dynamics MESH: Protein Conformation 0302 clinical medicine Humans MESH: Protein Binding MESH: Molecular Dynamics Simulation MESH: Hydrogen Bonding Receptor ComputingMilieux_MISCELLANEOUS 030304 developmental biology G protein-coupled receptor Ions 0303 health sciences MESH: Humans Chemistry Hydrogen bond Hydrogen Bonding General Chemistry Transmembrane protein Computer Science Applications Transmembrane domain Intramolecular force Helix Receptors Adrenergic beta-2 MESH: Receptors Adrenergic beta-2 [CHIM.CHEM]Chemical Sciences/Cheminformatics 030217 neurology & neurosurgery Protein Binding |
| Zdroj: | Journal of Chemical Information and Modeling Journal of Chemical Information and Modeling, American Chemical Society, 2019, 59 (9), pp.3611-3618. ⟨10.1021/acs.jcim.9b00054⟩ |
| ISSN: | 1549-960X 1549-9596 |
| DOI: | 10.1021/acs.jcim.9b00054 |
| Popis: | International audience; Over the past decade, the ever-growing structural information on G-protein coupled receptors (GPCRs) has revealed the three-dimensional (3D) characteristics of a receptor structure that is competent for G-protein binding. Structural markers are now commonly used to distinguish GPCR functional states, especially when analyzing molecular dynamics simulations. In particular, the position of the sixth helix within the seven transmembrane domains (TMs) is directly related to the coupling of the G-protein. Here, we show that the structural pattern defined by transmembrane intramolecular interactions (hydrogen bonds excluding backbone/backbone interactions, ionic bonds and aromatic interactions) is suitable for comparison of GPCR 3D structures and unsupervised distinction of the receptor states. First, we analyze a microsecond long molecular dynamic simulation of the human ß2-adrenergic receptor (ADRB2). Clustering of the 3D structures by pattern similarity identifies stable states which match the conformational classes defined by structural markers. Furthermore, the method directly spots the few state-specific interactions. Transforming pattern into graph, we extend the method to the comparison of different GPCRs. Clustering all GPCR experimentally determined structures by clique relative size first separates receptors, then their conformational states, thereby suggesting that the interaction patterns are specific of the receptor sequence and that the interaction signatures of conformational states are not shared across distant homologues. |
| Databáze: | OpenAIRE |
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