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: 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.