Computational Analysis of Histamine Protonation Effects on H1R Binding

Conrad M, Horn A, Sticht H (2023)

Publication Type: Journal article

Publication year: 2023

Journal

Molecules MDPI

Book Volume: 28

Article Number: 3774

Journal Issue: 9

DOI: 10.3390/molecules28093774

Abstract

Despite numerous studies investigating histamine and its receptors, the impact of histamine protonation states on binding to the histamine H (Formula presented.) -receptor (H (Formula presented.) R) has remained elusive. Therefore, we assessed the influence of different histamine tautomers ((Formula presented.) -tautomer, (Formula presented.) -tautomer) and charge states (mono- vs. dicationic) on the interaction with the ternary histamine-H (Formula presented.) R-Gq complex. In atomistic molecular dynamics simulations, the (Formula presented.) -tautomer formed stable interactions with the receptor, while the (Formula presented.) -tautomer induced a rotation of the histamine ring by 180° and formed only weaker hydrogen bonding interactions. This suggests that the (Formula presented.) -tautomer is more relevant for stabilization of the active ternary histamine-H (Formula presented.) R-Gq complex. In addition to the two monocationic tautomers, the binding of dicationic histamine was investigated, whose interaction with the H (Formula presented.) R had been observed in a previous experimental study. Our simulations showed that the dication is less compatible with the ternary histamine-H (Formula presented.) R-Gq complex and rather induces an inactive conformation in the absence of the Gq protein. Our data thus indicate that the charge state of histamine critically affects its interactions with the H (Formula presented.) R. Ultimately these findings might have implications for the future development of new ligands that stabilize distinct H (Formula presented.) R activation states.

Authors with CRIS profile

Marcus Conrad Professur für Bioinformatik Anselm Horn Professur für Bioinformatik Heinrich Sticht Professur für Bioinformatik

Additional Organisation(s)

Erlangen National High Performance Computing Center (NHR@FAU) FAU Forschungszentrum Neue Wirkstoffe (FAU NeW)

How to cite

APA:

Conrad, M., Horn, A., & Sticht, H. (2023). Computational Analysis of Histamine Protonation Effects on H1R Binding. Molecules, 28(9). https://doi.org/10.3390/molecules28093774

MLA:

Conrad, Marcus, Anselm Horn, and Heinrich Sticht. "Computational Analysis of Histamine Protonation Effects on H1R Binding." Molecules 28.9 (2023).

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