Hofmeister Series for Metal-Cation–RNA Interactions: The Interplay of Binding Affinity and Exchange Kinetics

[Image: see text] A large variety of physicochemical properties involving RNA depends on the type of metal cation present in solution. In order to gain microscopic insight into the origin of these ion specific effects, we apply molecular dynamics simulations to describe the interactions of metal cations and RNA. For the three most common ion binding sites on RNA, we calculate the binding affinities and exchange rates of eight different mono- and divalent metal cations. Our results reveal that binding sites involving phosphate groups preferentially bind metal cations with high charge density (such as Mg(2+)) in inner-sphere conformations while binding sites involving N7 or O6 atoms preferentially bind cations with low charge density (such as K(+)). The binding affinity therefore follows a direct Hofmeister series at the backbone but is reversed at the nucleobases leading to a high selectivity of ion binding sites on RNA. In addition, the exchange rates for cation binding cover almost 5 orders of magnitude, leading to a vastly different time scale for the lifetimes of contact pairs. Taken together, the site-specific binding affinities and the specific lifetime of contact pairs provide the microscopic explanation of ion specific effects observed in a wide variety of macroscopic RNA properties. Finally, combining the results from atomistic simulations with extended Poisson–Boltzmann theory allows us to predict the distribution of metal cations around double-stranded RNA at finite concentrations and to reproduce the results of ion counting experiments with good accuracy.