QM/MM investigation into binding of square-planar platinum complexes to DNA fragments

A series of calculations employing hybrid quantum mechanics/molecular mechanics methods to explore the binding of square-planar complexes to fragments of DNA are reported. Methylated analogues of the parent compound cis-[Pt(en)Cl(2)], where en is ethylenediamine, show considerable variation in in vitro cytotoxicity depending on the number and position of methyl groups. Calculations reveal variations in the structure and the binding energy of adducts to single- and double-stranded fragments of DNA. Most such variations are relatively small, but the introduction of three or four methyls on nitrogen of ethylenediamine significantly changes the structure and reduces the binding energy, owing to replacement of strong N-H...O interactions by much weaker C-H...O contacts. Close correlation between measured activity and binding energy is observed, whereas little or no correlation is found with structural parameters or with estimates of the octanol/water partition coefficient, either alone or in combination via multiple linear regression.