Magnesium ions mitigate metastable states in the regulatory landscape of mRNA elements

Ligand and Mg²⁺ binding help shift the population to the native, ligand-bound state in the free energy landscape in principal component PC1–PC2 space at 300 K. (A) Case without Mg²⁺ (0 mM Mg²⁺) and without ligand (dG[−]). (B) Case without Mg²⁺ (0 mM Mg²⁺) and with ligand (dG[+]). (C) Case with Mg²⁺ (5 mM Mg²⁺) and without ligand (dG[−]). (D) Case with Mg²⁺ (5 mM Mg²⁺) and with ligand (dG[+]). When ligand and Mg²⁺ are both absent, the energy landscape is rugged with the emergence of many metastable states. Upon the addition of Mg²⁺, the energy landscape becomes more confined, but the nonnative structures are still populated. However, the binding of the ligand eliminates the local minima and restrains the system in its native structure. With the presence of both ligand and Mg²⁺, the system shows a well-funneled energy landscape at the global minimum.