Theoretical Simulations on Interactions of Mono- and Dinuclear Metallonucleases with DNA

In the present study, molecular dynamic simulations have been performed to investigate the DNA binding affinities and cleavage activities of a new class of mononuclear copper (p-Cu(BPA) and m-Cu(BPA)) and dinuclear copper platinum (p-Cu(BPA)-Pt and m-Cu(BPA)-Pt) metallonucleases. The simulated results reveal that the two mononuclear nucleases are noncovalent minor groove DNA binders and the two dinuclear ones tend to be bound to DNA in the major groove by a covalent bond between the platinum center and N7 of the guanine base, which is in agreement with the experimental results. The simulated results show that the binding affinities of the four studied nucleases with DNA are in the order of p-Cu(BPA) < m-Cu(BPA) < p-Cu(BPA)-Pt < m-Cu(BPA)-Pt; the binding affinities are dominated by intermolecular binding modes of nucleases with DNA and the intermolecular hydrogen bonds. The distance probability distributions indicate that the hydrogen atoms of DNA sugar could be abstracted by the four nucleases. Specifically, the dinuclear nucleases abstract hydrogen atoms from the deoxyribose sugar linking to G(18) base while mononuclear nuclease abstracts hydrogen atoms from the deoxyribose sugars linking to C-15 and C-16 bases, suggesting that the dinuclear nucleases improve the sequence-selective cleavage of DNA compared with the mononuclear one. Moreover, the differences in calculated DNA conformational dynamics and groove parameters demonstrate that the extent of DNA conformational distortions induced by dinuclear nucleases is greater than that induced by mononuclear nucleases. This investigation provides detailed information showing that dinuclear nucleases have superior DNA binding affinities and nuclease activities as compared with their mononuclear counterparts.