Computational Analysis of Histamine Protonation Effects on H₁R Binding

Area of Science:

• Biochemistry
• Molecular Pharmacology
• Computational Chemistry

Background:

• Histamine receptors mediate diverse physiological processes.
• The precise role of histamine's protonation state in H1R binding remains unclear.
• Understanding histamine-H1R interactions is crucial for drug development.

Purpose of the Study:

• To investigate how histamine's tautomers and charge states affect binding to the histamine H1-receptor (H1R).
• To elucidate the molecular mechanisms underlying histamine-H1R-Gq complex formation.
• To provide insights for designing selective H1R modulators.

Main Methods:

• Atomistic molecular dynamics simulations.
• Analysis of histamine tautomers (τ- and π-) and charge states (monocationic and dicationic).
• Assessment of interactions within the ternary histamine-H1R-Gq complex.

Main Results:

• The τ-tautomer of histamine forms stable interactions with H1R, stabilizing the active complex.
• The π-tautomer exhibits weaker interactions and induces ring rotation.
• Dicationic histamine is incompatible with the ternary complex and promotes inactive conformations without Gq protein.

Conclusions:

• Histamine's charge state critically influences its binding affinity and efficacy at the H1R.
• The τ-tautomer is likely the key species for H1R activation.
• Findings may guide the development of ligands targeting specific H1R activation states.