Cisplatin cytotoxicity: a theoretical study of induced mutations.

We investigate possible mutations in the genetic code induced by cisplatin with an approach combining molecular dynamics (MD) and hybrid quantum mechanics/molecular mechanics (QM/MM) calculations. Specifically, the impact of platination on the natural tautomeric equilibrium in guanine-cytosine (GC) base pairs is assessed to disclose the possible role played by non-canonical forms in anti-tumour activity. To obtain valuable predictions, the main interactions present in a real DNA environment, namely hydration and stacking, are simultaneously taken into account. According to our results, the Pt-DNA adduct promotes a single proton transfer reaction in GC in the DNA sequence AG[combining low line]G[combining low line]C. Such rare tautomers might play an important role in the cisplatin biological activity since they meet the stability requirements necessary to promote a permanent mutation.