A Metadynamics-Based Protocol for the Determination of GPCR-Ligand Binding Modes

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Details zur Publikation

Autorinnen und Autoren: Söldner C, Horn A, Sticht H
Zeitschrift: International Journal of Molecular Sciences
Jahr der Veröffentlichung: 2019
Band: 20
Heftnummer: 8
ISSN: 1422-0067


G protein-coupled receptors (GPCRs) are a main drug target and therefore a hot topic in pharmaceutical research. One important prerequisite to understand how a certain ligand affects a GPCR is precise knowledge about its binding mode and the specific underlying interactions. If no crystal structure of the respective complex is available, computational methods can be used to deduce the binding site. One of them are metadynamics simulations which have the advantage of an enhanced sampling compared to conventional molecular dynamics simulations. However, the enhanced sampling of higher-energy states hampers identification of the preferred binding mode. Here, we present a novel protocol based on clustering of multiple walker metadynamics simulations which allows identifying the preferential binding mode from such conformational ensembles. We tested this strategy for three different model systems namely the histamine H1 receptor in combination with its physiological ligand histamine, as well as the β 2 adrenoceptor with its agonist adrenaline and its antagonist alprenolol. For all three systems, the proposed protocol was able to reproduce the correct binding mode known from the literature suggesting that the approach can more generally be applied to the prediction of GPCR ligand binding in future.

FAU-Autorinnen und Autoren / FAU-Herausgeberinnen und Herausgeber

Horn, Anselm Dr.
Lehrstuhl für Biochemie
Söldner, Christian
Professur für Bioinformatik
Sticht, Heinrich Prof. Dr.
Professur für Bioinformatik


Söldner, C., Horn, A., & Sticht, H. (2019). A Metadynamics-Based Protocol for the Determination of GPCR-Ligand Binding Modes. International Journal of Molecular Sciences, 20(8). https://dx.doi.org/10.3390/ijms20081970

Söldner, Christian, Anselm Horn, and Heinrich Sticht. "A Metadynamics-Based Protocol for the Determination of GPCR-Ligand Binding Modes." International Journal of Molecular Sciences 20.8 (2019).


Zuletzt aktualisiert 2019-24-05 um 15:38