Importance of diffuse metal ion binding to RNA

Abstract

RNAs are highly charged polyanionic molecules. RNA structure and function are strongly correlated with the ionic condition of the solution. The primary focus of this article is on the role of diffusive ions in RNA folding. Due to the long-range nature of electrostatic interactions, the diffuse ions can contribute significantly to RNA structural stability and folding kinetics. We present an overview of the experimental findings as well as the theoretical developments on the diffuse ion effects in RNA folding. This review places heavy emphasis on the effect of magnesium ions. Magnesium ions play a highly efficient role in stabilizing RNA tertiary structures and promoting tertiary structural folding. The highly efficient role goes beyond the mean-field effect such as the ionic strength. In addition to the effects of specific ion binding and ion dehydration, ion-ion correlation for the diffuse ions can contribute to the efficient role of the multivalent ions such as the magnesium ions in RNA folding.

Figure 1

(i) Modes a and b have an identical net average charge (= 0, i.e., neutral), but mode a has a much lower energy than mode b, causing the system to have higher tendency to stay in mode a. It is important to distinguish the different discrete ion distributions and the use of net average “charge neutralization” may not be appropriate. (ii) The likelihood of finding a positive or negative charge at a site (such as site 2) depends on the discrete distribution (locations) of all the other ions instead of the ensemble average distribution of the ions. (iii) A strongly correlated state (such as mode a) can reach much lower energy than a “mean” state. So correlation lowers the energy. Such a correlation-induced low energy effect is more pronounced for a folded RNA structure due to its higher RNA backbone charge density, leading to correlation-enhanced stabilization of the folded structure. Therefore, the unusual efficiency of Mg²⁺ ions, which can be strongly correlated, in RNA stabilization may be attributed to the enhanced stabilization effect due to correlation.

Figure 2

Illustration of the importance of diffuse ion binding in a two-helix system. A. The calculated electrostatic free energy ΔG(x)=G(x) – G(40 Å) as a function of the axis-axis distance x. B. The snapshots for the ion distributions around the helices at x=26 Å (top panel) and x=38 Å (bottom panel), respectively.