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Journal of Molecular Modeling

, 24:346 | Cite as

Binding of histamine to the H1 receptor—a molecular dynamics study

  • Christian A. Söldner
  • Anselm H. C. Horn
  • Heinrich Sticht
Original Paper
  • 126 Downloads
Part of the following topical collections:
  1. Tim Clark 70th Birthday Festschrift

Abstract

Binding of histamine to the G-protein coupled histamine H1 receptor plays an important role in the context of allergic reactions; however, no crystal structure of the resulting complex is available yet. To deduce the histamine binding site, we performed unbiased molecular dynamics (MD) simulations on a microsecond time scale, which allowed to monitor one binding event, in which particularly the residues of the extracellular loop 2 were involved in the initial recognition process. The final histamine binding pose in the orthosteric pocket is characterized by interactions with Asp1073.32, Tyr1083.33, Thr1945.43, Asn1985.46, Trp4286.48, Tyr4316.51, Phe4326.52, and Phe4356.55, which is in agreement with existing mutational data. The conformational stability of the obtained complex structure was subsequently confirmed in 2 μs equilibrium MD simulations, and a metadynamics simulation proved that the detected binding site represents an energy minimum. A complementary investigation of a D107A mutant, which has experimentally been shown to abolish ligand binding, revealed that this exchange results in a significantly weaker interaction and enhanced ligand dynamics. This finding underlines the importance of the electrostatic interaction between the histamine ammonium group and the side chain of Asp1073.32 for histamine binding.

Keywords

G-protein coupled receptors (GPCRs) Histamine Molecular dynamics simulations Metadynamics Receptor–ligand interactions Ligand binding Allergic reactions 

Notes

Acknowledgements

The authors gratefully acknowledge the computer resources and support provided by the Erlangen Regional Computing Center (RRZE) and the Leibniz Rechenzentrum, Munich. C.A.S. would like to thank Jonas Kaindl from the Computer-Chemie-Centrum (CCC) of the FAU Erlangen-Nürnberg for fruitful discussions and valuable advice. This paper is dedicated to Prof. Tim Clark, an eminent computational chemist, on the occasion of his 70th birthday.

Author Contributions

H.S. and C.A.S. conceived the study. A.H.C.H. and C.A.S. carried out the parametrization of histamine. C.A.S. performed the simulations and subsequent analyses. All authors interpreted the results and contributed to the manuscript.

Funding

The study was funded by Deutsche Forschungsgemeinschaft (DFG) in the graduate school Graduiertenkolleg GRK1910. In addition, the work was supported by a grant of computer time on SuperMUC at the Leibniz Rechenzentrum, Munich (project pr74su).

Compliance with Ethical Standards

Conflict of interest

The authors declare that they have no conflicts of interest.

Supplementary material

894_2018_3873_MOESM1_ESM.pdf (459 kb)
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894_2018_3873_MOESM2_ESM.mp4 (36.5 mb)
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894_2018_3873_MOESM7_ESM.pdb (365 kb)
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894_2018_3873_MOESM8_ESM.pdb (365 kb)
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Copyright information

© Springer-Verlag GmbH Germany, part of Springer Nature 2018

Authors and Affiliations

  1. 1.Bioinformatik, Institut für Biochemie, Emil-Fischer-Centrum, Friedrich-Alexander-Universität Erlangen-Nürnberg (FAU), ErlangenGermany

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