Molecular dynamics simulation and free energy perturbation studies of the minor groove of DNA: Structures and cation interactions

Different models for minor groove structures propose that the structure is essentially fixed by sequence and has no influence on local ion distribution or alternatively that dynamic motions of ions around the minor groove can affect the structure if they neutralize cross-strand phosphate repulsion. Molecular dynamics studies show that the minor groove in an AATT sequence responds to local sodium ion positions and is narrow when ions neutralize cross-strand phosphate-phosphate repulsion. Experimental results have shown that G-tracts often have a wider minor groove than A-tract sequences but they do not indicate whether this is due to reduced conformational flexibility or differences in ion interactions. The results show that the G-tract has the same amplitude of minor groove fluctuations as the A-tract sequence but that it has fewer ion interactions that neutralize cross-strand phosphate charges. These results clearly demonstrate that differences in average groove width between A- and G-tracts are due to differences in ion interactions at the minor groove. When ions neutralize the cross-strand phosphates, the minor groove is narrow. When there are no neutralizing ion interactions, the minor groove in wide. Furthermore, elimination of the phosphate-phosphate repulsion across the minor groove of the GGCC sequence by converting the central phosphate groups to the neutral methylphosphonate equivalent causes the minor groove to be narrow. Finally, molecular dynamics and free energy perturbation results show how small organic dicationic compounds can interact with the minor groove of DNA. The flexible nature of DNA molecules allows the minor groove to accommodate these compounds as both monomers and dimers forming specific hydrogen bond interactions between the compounds and the floor of the minor groove.