New regioselectivity in the cleavage of histidine-containing peptides by palladium(II) complexes studied by kinetic experiments and molecular dynamics simulations

Palladium(II) complexes promote hydrolytic cleavage of amide bonds in N-acetylhistidylglycine (AcHis−Gly), N-acetylhistidine (AcHis), and their derivatives methylated at the N-1 or N-3 atom of imidazole. Methylation controls coordination of imidazole to palladium(II) and allows stereochemical analysis of the reactions. The complex [PdCl4]2- regioselectively cleaves the amide bond involving the carboxylic group of histidine, the bond His−Gly; the rate constants of cleavage are virtually the same when the peptides coordinate to palladium(II) via the N-1 and the N-3 atom. The complex [Pd(H2O)4]2+ cleaves, at comparable rates, the amide bonds involving both the carboxylic (His−Gly) and the amino (AcHis) groups of histidine in the acetylated dipeptide. This unprecedented reactivity is examined by theoretical calculations in which molecular dynamics and solution of Poisson−Boltzmann equation are combined in a new way. When the Pd(H2O)32+ group is attached to the N-1 atom, both scissile bonds can be cleaved by i...