Organometallic ruthenium(II)-arene complexes are currently attracting increasing interest as anticancer compds. with the potential to overcome drawbacks of traditional drugs like cisplatin with respect to resistance, selectivity, and toxicity. Rational design of new potential pharmaceutical compds. requires a detailed understanding of structure-property relationships at an at. level. We performed in vacuo d. functional theory (DFT) calcns., classical MD, and mixed QM/MM Car-Parrinello MD explicit solvent simulations to rationalize the binding mode of two series of anticancer ruthenium(II) arene complexes to double-stranded DNA (dsDNA). Binding energies between the metal centers and the surrounding ligands as well as proton affinities were calcd. using DFT. Our results support a pH-dependent mechanism for the activity of the RAPTA [Ru(h6-arene)X2(pta)] (pta = 1,3,5-triaza-7-phosphatricyclo[3.3.1.1]decane) compds. Adducts of the bifunctional RAPTA and the monofunctional [Ru(h6-p-cymene)Xen]+ series of compds. with the DNA sequence d(CCTCTG*G*TCTCC)/d(GGAGACCAGAGG), where G* are guanosine bases that bind to the ruthenium compds. through their N(7) atom, have been investigated. The resulting binding sites were characterized in QM/MM mol. dynamics simulations showing that DNA can easily adapt to accommodate the ruthenium compds. [on SciFinder (R)]