Sequence Effects On Mg+2 Ion Mediated Dna - Dna Interactions

Ion mediated interactions between nucleic acids helices are essential for their efficient packaging within tight spaces such as viral capsids, sperm heads, and cell nuclei. However, the underlying physical principles at the molecular level are still debatable. In this study, we investigate the role of Mg+2 ions in sequence dependent DNA-DNA interaction within ordered dsDNA arrays, via an integrated approach of osmotic pressure measurements coupled with molecular dynamics simulations. Umbrella sampling simulations allowed computing the potential of mean force (PMF) between dsDNAs as a function of inter-DNA spacing and provided direct comparison to osmotic pressure measurements. The interaction of dsDNAs in MgCl2 are found to be repulsive in nature with two distinct regimes reflected by distance depended osmotic pressure curves. Interestingly, our study shows a strong dependence of these interactions with ion valency. Divalent ions demonstrated sequence specificity; an observation absent for the monovalent ions. In the presence of Mg2+ ions the interaction strength as measured by the change in free energy is found to be ‖d(A):d(T)|>|d(AT):d(TA)|>|Genomic DNA‖. Molecular simulations showed excellent agreement with experiments in each of the sequences studied and allowed us to decipher the underlying principles and molecular mechanism of the peculiar DNA sequence dependence. Our analysis revealed strong correlation between the structure of the counterion atmosphere and inter-DNA interaction. The strength of the interaction energy is found to be mediated by tightly bound Mg ions that show differences in each sequence studied. We further partition the interaction energy into thermodynamic potentials, and the results suggest a significant role of the solvent due to large changes in the translational entropy of cations and water during the dsDNA assembly.