Coordination chemistry of Co(II)-bleomycin: Its investigation through NMR and molecular dynamics

Previous studies on the coordination chemistry of Co-bleomycin have suggest ed the secondary amine in beta-aminoalanine, the N5 and N1 nitrogens in the pyrimidine and imidazole rings, respectively, and the amide nitrogen in be ta-hydroxyhistidine as equatorial ligands to the cobalt ion. The primary am ine in beta-aminoalanine and the carbamoyl group of the mannose have been p roposed alternatively as possible axial ligands, The first coordination sph ere of Co(II) in Co(II)BLM has been investigated in the present study throu gh the use of NMR and molecular dynamics calculations. The data collected f rom the NMR experiments are in agreement with the equatorial ligands previo usly proposed, and also support the participation of the primary amine as a n axial ligand. The paramagnetic shifts of the gulose and mannose protons c ould suggest the latter as a second axial ligand. This possibility was inve stigated by way of molecular dynamics, with distance restraints derived fro m the relaxation times measured through NMR. The molecular dynamics results indicate that the most favorable structure is six-coordinate, with the pri mary amine and either the carbamoyl oxygen or a solvent molecule occupying the axial sites. The analysis of the structures previously derived for HOO- Co(III)-bleomycin and HOO-Co(III) -peplcomycin led us to propose the six-co ordinate structure with only endogenous ligands, as the one held in solutio n by the Co(II) derivative of bleomycin.