Probing the role of surface structure in electrostatic interactions, we report the first observation of sequence-dependent dsDNA condensation by divalent alkali cations. Disparate behaviors were found between two repeating sequences with 100% AT content, a poly(A)-poly(T) duplex (AA-TT) and a poly(AT)-poly(TA) duplex (AT-TA). While AT-TA exhibits non-distinguishable behaviors from random-sequence genomic DNA, AA-TT condenses in all divalent alkali ions (Mg2+, Ca2+, Sr2+, and Ba2+). We characterized these interactions experimentally and investigated the underlying principles using all-atom computer simulations. Both experiment and simulation demonstrate that AA-TT condensation is driven by nonspecific ion-DNA interactions, which depend on the structures of ions and DNA surface. Detailed analyses reveal sequence-enhanced major groove binding (SEGB) of point-charged alkali ions as the major difference between AA-TT and AT-TA, which originates from the continuous and close stacking of nucleobase partial charges in AA-TT but not in AT-TA. These SEGB cations elicit attraction via spatial correlations with the phosphate backbone of neighboring helices, reminiscent of the DNA-zipper model, which though assumes a non-electrostatic cation groove binding a priori. Our study thus presents a distinct molecular mechanism of DNA-DNA interaction in which sequence-directed surface motifs act with abundant divalent alkali cations non-specifically to enact sequence-dependent behaviors. This physical insight allows a renewed understanding of the function of repeating DNA sequences in genome organization and regulation and offers a facile approach for DNA technology to control the assembly process of DNA nanostructures.

Structure-guided DNA-DNA attraction mediated by divalent cations