How Divalent Cations Interact with the Internal Channel Site of Guanine Quadruplexes

The formation of guanine quadruplexes (GQ) in DNA is crucial in telomere homeostasis and regulation of gene expression. Pollution metals can interfere with these DNA superstructures upon coordination. In this work, we study the affinity of the internal GQ channel site towards alkaline earth metal (Mg(2+), Ca(2+), Sr(2+), and Ba(2+)), and (post‐)transition metal (Zn(2+), Cd(2+), Hg(2+), and Pb(2+)) cations using density functional theory computations. We find that divalent cations generally bind to the GQ cavity with a higher affinity than conventional monovalent cations (e. g. K(+)). Importantly, we establish the nature of the cation‐GQ interaction and highlight the relationship between ionic and nuclear charge, and the electrostatic and covalent interactions. The covalent interaction strength plays an important role in the cation affinity and can be traced back to the relative stabilization of cations’ unoccupied atomic orbitals. Overall, our findings contribute to a deeper understanding of how pollution metals could induce genomic instability.