Effect Of The Cation Size On The Stability Of Rna Structures

The folding and subsequent stabilization of functional RNA structures depend strongly on the electrostatic screening of the negative charges on the phosphate group by alkali and alkaline earth metal ions. Such cations can either bind to structurally well-defined RNA sites or form a so-called ion cloud around RNA. However, it is difficult to directly observe these ions experimentally. The common view is that sodium ion is better in stabilizing RNA secondary structural elements than potassium ion that possess the same valance but a larger hydrodynamic radius. Mechanisms proposed to explain the additional stability imparted by sodium ions do not provide atomic details. We performed all-atom molecular dynamics (MD) simulation to distinguish between the effect of sodium and potassium on the stability of RNA. The free energy landscape of HIV-1 TAR was explored via MD simulations employing umbrella sampling along the mechanical pulling coordinate covering folded and unfolded states. Excellent agreement is obtained when our simulations are compared with experiments to validate our findings. Our extensive analysis of the structural and energetic details of RNA-ion interactions unveiled electrostatic screening as the reason for the extra stability. Unlike the common view, that monovalent ions form a uniform distribution around RNA, we observe discrete binding sites for monovalent ions. These sites are dynamically coupled with RNA conformations and show that the differences in charge density also explains the differences in the stability. High charge density Na+ binds preferentially to the backbone and screens the highly charged phosphates non-specifically. In contrast, large size K+ interacts weakly with phosphates. Instead, they associate at the major grooves as RNA secondary structures form, resulting in rather poor electrostatic stabilization. Overall, our results provide a molecular basis for understanding the interaction of monovalent cations with RNA molecules.