Induced ion correlations lead to DNA attraction in manganese

Divalent counterions show the ion specificity effect. In a free solution, Mn2+ ions can condense DNA into a disorder bundle of structures while the same valence Mg2+ ions dissolve DNA assemblies. Theoretical models were proposed to explain the Mn2+-induced condensation of DNA with limited success. Here, we employ all-atom molecular simulations to investigate the ion specificity effect on DNA-DNA interactions. An exhaustive sampling of inter-helical distance and angular orientations afforded by metadynamics simulations allowed us to construct the free energy surface of the DNA-DNA interactions. In excellent agreement with experiments, we observe that dsDNA strands show attraction in the presence of Mn2+, while they remain repulsive at the same ionic strength in MgCl2. To explain the disparate behavior of the two divalent cations, we investigate cation distributions and preferential binding sites. We observe significant differences in binding modes between Mn2+ and Mg2+. The manganese ions bind prevalently to the phosphate backbone, while magnesium ions occupy both backbone and the major groove of the DNA. We develop a simple like-charge attraction model based on the preferential binding sites derived from simulations. Our model explains the observed differences between the two cations successfully. It highlights the importance of induced ion correlations between adjacent pairs as the mechanism leading to attraction. Our results shed light into Mn2+ induced like charge attraction mechanism of DNA. The method can be extended to study other condensing agents.