DFT Study of the Metal Coordination Center Domain of Fe(II)−Bleomycin

Abstract

We present a comprehensive analysis of the geometric and electronic properties of the metal coordination center domain of the iron(II) complex of the antitumor drug bleomycin (BLM) using density functional theory (DFT). The various experimental studies devoted to establishing the nature of the metal coordination center in BLM suggest that the metal is five-coordinated, with a sixth site available for exogenous ligand binding. Among the five ligands, four of them form an equatorial coordination sphere, but the nature of the fifth axial ligand remains controversial. To elucidate the nature of the metal coordination center in Fe(II)−BLM, six structurally different conformers resembling the active site have been investigated using DFT. An optimal geometry has been found for each conformer in the singlet, triplet, and quintet electronic states. The electronic ground state was identified as a four-coordinate species with intermediate spin state. However, when the results of these calculations were compared with the latest 2D NMR data, the best agreement was found between the five-coordinated theoretical model and experiment. Stereoelectronic analysis of four-coordinate conformers has shown that the Fe out-of-plane displacement controls the spin state. The high-spin state potential energy surface intersects the triplet state potential energy surface along the doming-mode coordinate when the iron atom is displaced about 0.4 Å from the equatorial nitrogens average plane. This intersection is the result of different iron d orbital occupancy in quintet and triplet electronic states.