On the nature of ion‐stabilized cytosine pairs in DNA i‐motifs: The importance of charge transfer processes

Recent experimental results indicate that the stability of non‐Watson‐Crick DNA i‐motif structures can be influenced by the presence of various metal cations. Whereas Au+, Cu+, and Ag+ are stabilizing agents, alkali metal ions like Na+ or Li+ are known to destabilize the i‐motif. In terms of reduced ion‐cytosine complexes, we rationalize the experimental observations with the help of standard and conceptual density functional theory (DFT) calculations. Our results highlight the importance of coordinating electrostatic bonds with partially covalent character for the stability of the ion‐cytosine complex. The occurrence of these bonds can be mainly attributed to charge transfer processes between two cytosines and the transition metal ions, which can be either explained by frontier molecular orbital theory in combination with a bond critical point analysis, or by the concept of chemical reactivity indices within a conceptual DFT approach. The results of our calculations establish a consistent theoretical framework to understand the experimentally observed behavior, and are also important in order to achieve more detailed insights into nucleobase pairing mechanisms in general. The manuscript reports computational results concerning the molecular properties of cation‐stabilized cytosine pairs in DNA i‐motifs. The stability of modified i‐motif structures was recently discussed in the context of oncogenesis and modern drug development in cancer research. The outcomes of density functional theory calculations provide physical explanations for stable DNA i‐motifs including transition metal cations in contrast to unstable alkali metal ion complexes, also observed in previous experimental studies.