The stability of RNA increases as the charge density of the alkali metal cations increases. The molecular mechanism for this phenomenon remains elusive. To fill this gap, we performed all-atom molecular dynamics pulling simulations of HIV-1 trans-activation response RNA. We first established that the free energy landscape obtained in the simulations is in excellent agreement with the single-molecule optical tweezer experiments. The origin of the stronger stability in sodium compared to potassium is found to be due to the differences in the charge density–related binding modes. The smaller hydrated sodium ion preferentially binds to the highly charged phosphates that have high surface area. In contrast, the larger potassium ions interact with the major grooves. As a result, more cations condense around phosphate groups in the case of sodium ions, leading to the reduction of electrostatic repulsion. Because the proposed mechanism is generic, we predict that the same conclusions are valid for divalent alkaline earth metal cations.
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