Computational Analysis of Histamine Protonation Effects on H₁R Binding

Despite numerous studies investigating histamine and its receptors, the impact of histamine protonation states on binding to the histamine H-1-receptor (H1R) has remained elusive. Therefore, we assessed the influence of different histamine tautomers (tau-tautomer, pi-tautomer) and charge states (mono- vs. dicationic) on the interaction with the ternary histamine-H1R-Gq complex. In atomistic molecular dynamics simulations, the tau-tautomer formed stable interactions with the receptor, while the pi-tautomer induced a rotation of the histamine ring by 180 degrees and formed only weaker hydrogen bonding interactions. This suggests that the tau-tautomer is more relevant for stabilization of the active ternary histamine-H1R-Gq complex. In addition to the two monocationic tautomers, the binding of dicationic histamine was investigated, whose interaction with the H1R had been observed in a previous experimental study. Our simulations showed that the dication is less compatible with the ternary histamine-H1R-Gq 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 H1R. Ultimately these findings might have implications for the future development of new ligands that stabilize distinct H1R activation states.