Computational Analysis of Histamine Protonation Effects on H1R Binding

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.