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-ace tylhistidylglycine (AcHis-Gly), N-acetylhistidine (AcHis), and their deriva tives methylated at the N-1 or N-3 atom of imidazole. Methylation controls coordination of imidazole to palladium(II) and allows stereochemical analys is of the reactions. The complex [PdCl4](2-) regioselectively cleaves the a mide bond involving the carboxylic group of histidine, the bond His-Gly; th e rate constants of cleavage are virtually the same when the peptides coord inate 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 car boxylic (His-Gly) and the amino (AcHis) groups of histidine in the acetylat ed dipeptide. This unprecedented reactivity is examined by theoretical calc ulations in which molecular dynamics and solution of Poisson-Boltzmann equa tion are combined in a new way. When the Pd(H2O)(3)(2+) group is attached t o the N-1 atom, both scissile bonds can be cleaved by internal delivery of aqua ligands. When the Pd(H2O)(3)(2+) group is attached to the N-3 atom, bo th scissile bonds can be cleaved by internal delivery of aqua ligands and b y external attack of water; in some conformers the two modes of cleavage ma y be combined in the reaction mechanism. In both N-1 and N-3 linkage isomer s internal delivery seems to be assisted by weak hydrogen bonding. The rate constants for cleavage by [Pd(H2O)(4)](2+) are approximately 10 times grea ter than those for cleavage by [PdCl4](2-). This difference is explained se miquantitatively by consideration of the aquation equilibria involving [PdC l4](2-). This study shows that kinetics and regioselectivity of peptide cle avage may be controlled simply by choosing ligands in palladium(II) complex es. This is another step in our development of simple metal complexes as ar tificial metallopeptidases.