Ion dependent stability of RNA three-way junction and DNA triple helices

Abstract

[ACCESS RESTRICTED TO THE UNIVERSITY OF MISSOURI AT REQUEST OF AUTHOR.] Nucleic acids are critical for regulation of gene expression. Because nucleic acid molecules are highly charged, the folding of nucleic acids involves massive charge build-up. The counterions would neutralize the negative charges on nucleic acids and screen the Coulomb repulsion between the different parts of the nucleic acids. Thus, ions can provide a significant stabilizing force in nucleic acid folding. Although considerable progress has been made in the studies of ion electrostatic interaction in nucleic acid folding, the current theoretical models are unable to predict ion effects in nucleic acid folding. One of the key issues that cannot be addressed is the effect of ion correlation, which is significant in Mg2+-nucleic acid interactions. We develop a new model, called the tightly bound ion (TBI) model, to predict ion effects in nucleic acid folding by accounting for the ion correlation effect. Extensive experimental comparisons have shown that, our TBI model can indeed lead to notable improvements in the predictions of the ion-dependent stability of nucleic acids. As an application, we employ the TBI model to investigate the ion-dependent free energy landscape for the RNA three-way junction. The TBI-predicted folding stability agrees quantitatively with the experimental measurements. As a further application of the model, we apply the TBI model to investigate the ion-dependent stability of DNA triple helices. By calculating the free energy landscape of a pair of triple helices immersed in an ionic solution, we first demonstrated divalent ions induced condensation of triple-strand DNA theoretically. Besides, the positive charges on the protonated cytosine residues in the third strand lead to a sequence-dependent electrostatic contribution to triplex stability. We calculated electrostatic free energies for different sequence of triplexes and compared the sequence dependent electrostatic free energy to the experimental measured melting temperature. Our TBI model predicted sequence dependent stability of DNA triplex agrees well with the experimental results.