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

Sergio Cruz-León,Nadine Schwierz

doi:10.1021/acs.langmuir.0c00851

Sergio Cruz-León, Nadine Schwierz

Open Access

https://doi.org/10.1021/acs.langmuir.0c00851

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Abstract

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 Mg2+) 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.

Highlights

Metal cations are essential for the folding and function of nucleic acids
Predicting how metal cations affect the physicochemical properties of RNA is challenging due to the entangled contributions of backbone, nucleobases, ions, and water
The results clearly reveal which metal ion preferentially binds to the phosphate or nucleobase binding site and whether the interaction involves an inner- or outer-sphere contact (Table 2)

Summary

Introduction

Metal cations are essential for the folding and function of nucleic acids. Given the negative charge of the sugar−phosphate backbone, positively charged ions are required to screen the electrostatic interactions. Metal cation binding to specific sites stabilizes the three-dimensional structure further and assists or even enables catalytic reactions, for instance, in ribozymes. The folded structure of large ribozymes is stabilized most efficiently by Mg2+ ions while the stabilization efficiency decreases with decreasing charge density of the ions.[1−4] On the other hand, the folding kinetics is 20−40-fold faster if Mg2+ ions are replaced by Ba2+ or Na+ ions,[14] indicating competing effects in thermodynamic stabilization and folding kinetics. Such ion specific effects are ubiquitous and known for a large variety of physical properties such as osmotic coefficients, solubility of gases and colloids, protein precipitation, or the catalysis of chemical reactions.[26] In most cases, anions and cations can be ranked reproducibly in a Hofmeister series according to their influence on these macroscopic properties.[27] At the same time, the widespread applicability of the Hofmeister series suggests that ion specific phenomena have a common origin. We know that water structuring effects and direct ion−macromolecule interactions are important.[28−30] in order to gain microscopic insights into the origin of ion specific effects in RNA systems, a quantitative description of cation− RNA interactions is required

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Results

Conclusion