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 AC. 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.