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Despite numerous studies investigating histamine and its receptors, the impact of histamine protonation states on binding to the histamine H<inline-formula><math xmlns="http://www.w3.org/1998/Math/MathML" display="inline"><semantics><msub><mrow></mrow><mn>1</mn></msub></semantics></math></inline-formula>-receptor (H<inline-formula><math xmlns="http://www.w3.org/1998/Math/MathML" display="inline"><semantics><msub><mrow></mrow><mn>1</mn></msub></semantics></math></inline-formula>R) has remained elusive. Therefore, we assessed the influence of different histamine tautomers (<inline-formula><math xmlns="http://www.w3.org/1998/Math/MathML" display="inline"><semantics><mi mathvariant="sans-serif">τ</mi></semantics></math></inline-formula>-tautomer, <inline-formula><math xmlns="http://www.w3.org/1998/Math/MathML" display="inline"><semantics><mi mathvariant="sans-serif">π</mi></semantics></math></inline-formula>-tautomer) and charge states (mono- vs. dicationic) on the interaction with the ternary histamine-H<inline-formula><math xmlns="http://www.w3.org/1998/Math/MathML" display="inline"><semantics><msub><mrow></mrow><mn>1</mn></msub></semantics></math></inline-formula>R-G_q complex. In atomistic molecular dynamics simulations, the <inline-formula><math xmlns="http://www.w3.org/1998/Math/MathML" display="inline"><semantics><mi mathvariant="sans-serif">τ</mi></semantics></math></inline-formula>-tautomer formed stable interactions with the receptor, while the <inline-formula><math xmlns="http://www.w3.org/1998/Math/MathML" display="inline"><semantics><mi mathvariant="sans-serif">π</mi></semantics></math></inline-formula>-tautomer induced a rotation of the histamine ring by 180° and formed only weaker hydrogen bonding interactions. This suggests that the <inline-formula><math xmlns="http://www.w3.org/1998/Math/MathML" display="inline"><semantics><mi mathvariant="sans-serif">τ</mi></semantics></math></inline-formula>-tautomer is more relevant for stabilization of the active ternary histamine-H<inline-formula><math xmlns="http://www.w3.org/1998/Math/MathML" display="inline"><semantics><msub><mrow></mrow><mn>1</mn></msub></semantics></math></inline-formula>R-G_q complex. In addition to the two monocationic tautomers, the binding of dicationic histamine was investigated, whose interaction with the H<inline-formula><math xmlns="http://www.w3.org/1998/Math/MathML" display="inline"><semantics><msub><mrow></mrow><mn>1</mn></msub></semantics></math></inline-formula>R had been observed in a previous experimental study. Our simulations showed that the dication is less compatible with the ternary histamine-H<inline-formula><math xmlns="http://www.w3.org/1998/Math/MathML" display="inline"><semantics><msub><mrow></mrow><mn>1</mn></msub></semantics></math></inline-formula>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<inline-formula><math xmlns="http://www.w3.org/1998/Math/MathML" display="inline"><semantics><msub><mrow></mrow><mn>1</mn></msub></semantics></math></inline-formula>R. Ultimately these findings might have implications for the future development of new ligands that stabilize distinct H<inline-formula><math xmlns="http://www.w3.org/1998/Math/MathML" display="inline"><semantics><msub><mrow></mrow><mn>1</mn></msub></semantics></math></inline-formula>R activation states.