Theoretical Simulationson Interactions of Mono- and Dinuclear Metallonucleases with DNA.

In the present study, molecular dynamic simulations havebeen performed to investigate the DNA binding affinities and cleavageactivities 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 mononuclearnucleases are noncovalent minor groove DNA binders and the two dinuclearones tend to be bound to DNA in the major groove by a covalent bondbetween the platinum center and N7 of the guanine base, which is inagreement with the experimental results. The simulated results showthat the binding affinities of the four studied nucleases with DNAare in the order of p-Cu(BPA) < m-Cu(BPA) < p-Cu(BPA)-Pt < m-Cu(BPA)-Pt; the binding affinities are dominated by intermolecularbinding modes of nucleases with DNA and the intermolecular hydrogenbonds. The distance probability distributions indicate that the hydrogenatoms of DNA sugar could be abstracted by the four nucleases. Specifically,the dinuclear nucleases abstract hydrogen atoms from the deoxyribosesugar linking to G18base while mononuclear nuclease abstractshydrogen atoms from the deoxyribose sugars linking to C15and C16bases, suggesting that the dinuclear nucleasesimprove the sequence-selective cleavage of DNA compared with the mononuclearone. Moreover, the differences in calculated DNA conformational dynamicsand groove parameters demonstrate that the extent of DNA conformationaldistortions induced by dinuclear nucleases is greater than that inducedby mononuclear nucleases. This investigation provides detailed informationshowing that dinuclear nucleases have superior DNA binding affinitiesand nuclease activities as compared with their mononuclear counterparts. [ABSTRACT FROM AUTHOR]