Metal complex–DNA binding: Insights from molecular dynamics and DFT/MM calculations

• [Cu(gly)(dppz)]+ (1) is a DNA-intercalator with promising anticancer properties
• The DNA-binding of 1 was investigated by MD and DFT/MM calculations
• Structural and energetic details of the 1-DNA supramolecular complexes were obtained
• 1-DNA binding occurs by metal coordination, intercalation and hydrogen bonding
• 1 has higher affinity for AT than for GC sequences.

Molecular dynamics (MD) simulations, followed by density functional theory/molecular mechanics (DFT/MM) calculations, provided a detailed structure of the binding site between the cationic metallointercalator (dipyrido [3,2-a:2′,3′-c]phenazine)(glycinato)copper(II), [Cu(gly)(dppz)]+, and the two dodeca-deoxynucleotide duplexes [dodeca(dG-dC)]2 and [dodeca(dA-dT)]2. Three simultaneous DNA binding types were detected in the fully optimized DFT/MM structures: 1) metal coordination through exocyclic oxygen atoms of nitrogen bases; 2) intercalation of the dppz chromophore between stacked Watson–Crick AT–AT and GC–GC bases; and 3) hydrogen bonding between the glycinato ligand and amine groups or heterocyclic nitrogen atoms of DNA bases. Standard enthalpy and Gibbs free energy values were used to evaluate, in vacuo and in solution, the formation energy of both [Cu(gly)(dppz)]/dodecanucleotide complexes. The latter were in excellent agreement with the recently reported value of the experimental DNA-binding constant, providing a physical interpretation of the enthalpy, entropy and solvent contributions in the binding mechanism.

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