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Article

Agonist Binding and G Protein Coupling in Histamine H2 Receptor: A Molecular Dynamics Study

1
Bioinformatik, Institut für Biochemie, Emil-Fischer-Centrum, Friedrich-Alexander-Universität Erlangen-Nürnberg (FAU), Fahrstraße 17, 91054 Erlangen, Germany
2
Department of Computational Biology and Molecular Biosciences, University of Kansas, Lawrence, KS 66047, USA
*
Author to whom correspondence should be addressed.
Int. J. Mol. Sci. 2020, 21(18), 6693; https://doi.org/10.3390/ijms21186693
Submission received: 20 August 2020 / Revised: 4 September 2020 / Accepted: 8 September 2020 / Published: 12 September 2020
(This article belongs to the Special Issue Computer Simulation on Membrane Receptors and Lipid Bilayers)

Abstract

The histamine H2 receptor (H2R) plays an important role in the regulation of gastric acid secretion. Therefore, it is a main drug target for the treatment of gastroesophageal reflux or peptic ulcer disease. However, there is as of yet no 3D-structural information available hampering a mechanistic understanding of H2R. Therefore, we created a model of the histamine-H2R-Gs complex based on the structure of the ternary complex of the β2-adrenoceptor and investigated the conformational stability of this active GPCR conformation. Since the physiologically relevant motions with respect to ligand binding and conformational changes of GPCRs can only partly be assessed on the timescale of conventional MD (cMD) simulations, we also applied metadynamics and Gaussian accelerated molecular dynamics (GaMD) simulations. A multiple walker metadynamics simulation in combination with cMD was applied for the determination of the histamine binding mode. The preferential binding pose detected is in good agreement with previous data from site directed mutagenesis and provides a basis for rational ligand design. Inspection of the H2R-Gs interface reveals a network of polar interactions that may contribute to H2R coupling selectivity. The cMD and GaMD simulations demonstrate that the active conformation is retained on a μs-timescale in the ternary histamine-H2R-Gs complex and in a truncated complex that contains only Gs helix α5 instead of the entire G protein. In contrast, histamine alone is unable to stabilize the active conformation, which is in line with previous studies of other GPCRs.
Keywords: receptor–ligand interactions; G protein-coupled receptors (GPCRs); Gs protein; ternary complex; molecular dynamics simulations; metadynamics; Gaussian accelerated simulations (GaMD); ligand binding mode; gastric acid related diseases receptor–ligand interactions; G protein-coupled receptors (GPCRs); Gs protein; ternary complex; molecular dynamics simulations; metadynamics; Gaussian accelerated simulations (GaMD); ligand binding mode; gastric acid related diseases

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MDPI and ACS Style

Conrad, M.; Söldner, C.A.; Miao, Y.; Sticht, H. Agonist Binding and G Protein Coupling in Histamine H2 Receptor: A Molecular Dynamics Study. Int. J. Mol. Sci. 2020, 21, 6693. https://doi.org/10.3390/ijms21186693

AMA Style

Conrad M, Söldner CA, Miao Y, Sticht H. Agonist Binding and G Protein Coupling in Histamine H2 Receptor: A Molecular Dynamics Study. International Journal of Molecular Sciences. 2020; 21(18):6693. https://doi.org/10.3390/ijms21186693

Chicago/Turabian Style

Conrad, Marcus, Christian A. Söldner, Yinglong Miao, and Heinrich Sticht. 2020. "Agonist Binding and G Protein Coupling in Histamine H2 Receptor: A Molecular Dynamics Study" International Journal of Molecular Sciences 21, no. 18: 6693. https://doi.org/10.3390/ijms21186693

APA Style

Conrad, M., Söldner, C. A., Miao, Y., & Sticht, H. (2020). Agonist Binding and G Protein Coupling in Histamine H2 Receptor: A Molecular Dynamics Study. International Journal of Molecular Sciences, 21(18), 6693. https://doi.org/10.3390/ijms21186693

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