Imidazole geometry and the calculation of tautomer preference for histamine

In view of the implication of tautomeric change as part of the mechanism of histamine action at H2 receptors, the effect of such change on imidazole ring geometry is investigated. Crystal structure data and theoretical calculations suggest that the two tautomers have distinctly different ring geometries. Using appropriate tautomer geometries, ab initio molecular orbital calculations indicate that, for the isolated molecule, the N(tau)-H tautomer is prefered for histamine monocation but there is no clear tautomer preference for histamine base. Comparison with measurements on aqueous solutions suggests that water has a much greater influence on tautomer stability for the monocation than for the uncharged base.