Preferential Interactions of Charged and Neutral Cosolutes with a Model RNA Hairpin

Cosolutes, including neutral salts and denaturants, can profoundly stabilize different configurations of RNA or induce denaturation. Salient preferential interactions between RNA and solution species can be assessed through all-atom molecular dynamics (MD) simulations. At equilibrium, these simulations allow preferential interactions to be linked to experimental observations including cosolute distributions in vapor pressure osmometry and Donnan equilibrium measurements. In this work we describe preferential interactions between charged and neutral cosolute species (K+/Cl- and urea) and their interactions with an RNA sequence that forms a hyperstable GCAA tetraloop using isothermal (NVT) MD simulations. The RNA-KCl preferential interactions (Donnan coefficients) are determined at cellular (∼100 mM) and high (1-3 M) salt concentrations, and show an unexpected linear concentration dependence. At 3 M KCl, the Donnan coefficient is zero. In high (2-6 M) concentrations of urea, KCl preferentially excludes urea, while RNA preferentially attracts urea. Interestingly, despite the depletion of urea around KCl, the RNA-KCl preferential interaction increases. These results offer new insight into the interactions between RNA and many of the cosolute species that affect RNA folding in vivo.