Molecular Simulations of Ion Effects on the Thermodynamics of RNA Folding

How ions affect RNA folding thermodynamics and kinetics is an important but a vexing problem that remains unsolved. Experiments have shown that the free-energy change, ΔG(c), of RNA upon folding varies with the salt concentration (c) as, ΔG(c) = kc ln c + const, where the coefficient kc is proportional to the difference in the ion preferential coefficient, ΔΓ. We performed simulations of a coarse-grained model, by modeling electrostatic interactions implicitly and with explicit representation of ions, to elucidate the molecular underpinnings of the relationship between ΔG and ΔΓ. The simulations quantitatively reproduce the heat capacity for a pseudoknot, thus validating the model. We show that ΔG(c), calculated directly from ΔΓ, varies linearly with ln c (c < 0.2 M), for a hairpin and the pseudoknot, demonstrating a molecular link between the two quantities. Explicit ion simulations also show the linear dependence of ΔG(c) on ln c at all c with kc = 2kBT, except that ΔG(c) values are shifted by ∼2 kcal/m...