Molecular modeling of the three-dimensional structure of Fe(II)-bleomycin: are the Co(II) and Fe(II) adducts isostructural?

Abstract.

The molecular modeling of Co(II)-bleomycin previously performed by us through NMR and molecular dynamics indicates that the most favorable structure for this complex is six-coordinate, with the secondary amine in β-aminoalanine, the N5 and N1 nitrogens in the pyrimidine and imidazole rings, respectively, and the amide nitrogen in β-hydroxyhistidine as equatorial ligands. The primary amine and either the carbamoyl group or a solvent molecule are proposed to occupy the axial sites. In this report, the results of the molecular modeling of Fe(II)-bleomycin are presented. The NMR data for the ferrous derivative of the drug have already been reported by us, and were used here to generate the necessary restraints for this modeling work. For Co(II)-bleomycin, two new models exhibiting N-carbamoyl ligation to the metal centers were also assayed and compared with the ones previously examined. The results of this investigation on Fe(II)- and Co(II)-bleomycin are most consistent with a six-coordinate structure with five endogenous N-donors and a solvent molecule or the carbamoyl group as the sixth ligand. Comparisons of the best Co(II)- and Fe(II)-bleomycin models with the NMR-generated structures for some relevant metallo-BLMs favor the model with only endogenous ligands and N-carbamoyl ligation as the structure probably held in solution by both Co(II)- and Fe(II)-bleomycin.