Attracting Opposites: Promiscuous Ion-π Binding in the DNA Nucleobases

Ion-π interactions between the face of a molecular π-system and a cation or anion are among the strongest non-covalent interactions known, with applications throughout biochemistry and structural biology, host-guest chemistry, as well as enzyme kinetics and organocatalysis. In this work, we perform a detailed theoretical case study of ion-π interactions in the DNA/RNA nucleobases by first demonstrating that these π-systems are promiscuous ion-π binders with the versatility to bind both cations (Li⁺/Na⁺) and anions (F^-/Cl^-). Using a novel SAPT-based energy decomposition analysis, we uncover the different physicochemical driving forces underlying the formation of cation- and anion-π complexes, as well as the crucial role played by charge penetration effects in anion-π systems. In doing so, a unified view of these rather distinct non-covalent binding motifs emerges with the finding that both cation- and anion-π complexes are strongly stabilized by an essentially ring-independent potential that can only be overcome by substantially unfavorable electrostatics. Interestingly, the analysis presented herein demonstrates that π-systems have an inherent propensity to bind both cations and anions, thereby implying that promiscuous ion-π binding should be quite common in nature.