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Computational Analysis of Histamine Protonation Effects on H(1)R Binding

Despite numerous studies investigating histamine and its receptors, the impact of histamine protonation states on binding to the histamine H [Formula: see text]-receptor (H [Formula: see text] R) has remained elusive. Therefore, we assessed the influence of different histamine tautomers ([Formula: s...

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Detalles Bibliográficos
Autores principales: Conrad, Marcus, Horn, Anselm H. C., Sticht, Heinrich
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2023
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10180022/
https://www.ncbi.nlm.nih.gov/pubmed/37175183
http://dx.doi.org/10.3390/molecules28093774
Descripción
Sumario:Despite numerous studies investigating histamine and its receptors, the impact of histamine protonation states on binding to the histamine H [Formula: see text]-receptor (H [Formula: see text] R) has remained elusive. Therefore, we assessed the influence of different histamine tautomers ([Formula: see text]-tautomer, [Formula: see text]-tautomer) and charge states (mono- vs. dicationic) on the interaction with the ternary histamine-H [Formula: see text] R-G(q) complex. In atomistic molecular dynamics simulations, the [Formula: see text]-tautomer formed stable interactions with the receptor, while the [Formula: see text]-tautomer induced a rotation of the histamine ring by 180° and formed only weaker hydrogen bonding interactions. This suggests that the [Formula: see text]-tautomer is more relevant for stabilization of the active ternary histamine-H [Formula: see text] R-G(q) complex. In addition to the two monocationic tautomers, the binding of dicationic histamine was investigated, whose interaction with the H [Formula: see text] R had been observed in a previous experimental study. Our simulations showed that the dication is less compatible with the ternary histamine-H [Formula: see text] R-G(q) complex and rather induces an inactive conformation in the absence of the G(q) protein. Our data thus indicate that the charge state of histamine critically affects its interactions with the H [Formula: see text] R. Ultimately these findings might have implications for the future development of new ligands that stabilize distinct H [Formula: see text] R activation states.