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Contributions and competition of Mg²⁺ and K⁺ in folding and stabilization of the Twister ribozyme.

ABSTRACT: Native folded and compact intermediate states of RNA typically involve tertiary structures in the presence of divalent ions such as Mg²⁺ in a background of monovalent ions. In a recent study, we have shown how the presence of Mg²⁺ impacts the transition from partially unfolded to folded states through a "push-pull" mechanism where the ion both favors and disfavors the sampling of specific phosphate-phosphate interactions. To further understand the ion atmosphere of RNA in folded and partially folded states results from atomistic umbrella sampling and oscillating chemical potential grand canonical Monte Carlo/molecular dynamics (GCMC/MD) simulations are used to obtain atomic-level details of the distributions of Mg²⁺ and K⁺ ions around Twister RNA. Results show the presence of 100 mM Mg²⁺ to lead to increased charge neutralization over that predicted by counterion condensation theory. Upon going from partially unfolded to folded states, overall charge neutralization increases at all studied ion concentrations that, while associated with an increase in the number of direct ion-phosphate interactions, is fully accounted for by the monovalent K⁺ ions. Furthermore, K⁺ preferentially interacts with purine N7 atoms of helical regions in partially unfolded states, thereby potentially stabilizing the helical regions. Thus, both secondary helical structures and formation of tertiary structures leads to increased counterion condensation, thereby stabilizing those structural features of Twister. Notably, it is shown that K⁺ can act as a surrogate for Mg²⁺ by participating in specific interactions with nonsequential phosphate pairs that occur in the folded state, explaining the ability of Twister to self-cleave at submillimolar Mg²⁺ concentrations.

SUBMITTER: Kognole AA

PROVIDER: S-EPMC7566569 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:Metal ions, particularly magnesium ions (Mg2+), play a role in stabilizing the tertiary structures of RNA molecules. Theoretical models and experimental techniques show that metal ions can change RNA dynamics and how it transitions through different stages of folding. However, the specific ways in which metal ions contribute to the formation and stabilization of RNA's tertiary structure are not fully understood at the atomic level. Here, we combined oscillating excess chemical potential Grand Canonical Monte Carlo (GCMC) and metadynamics to bias toward the sampling of unfolded states using reaction coordinates generated by machine learning allowing for examination of Mg2+-RNA interactions that contribute to stabilizing folded states of the pseudoknot found in the Twister ribozyme. GCMC is used to sample diverse ion distributions around the RNA with deep learning applied to iteratively generate system-specific reaction coordinates to maximize conformational sampling during metadynamics simulations. Results from 6 μs simulations performed on 9 individual systems indicate that Mg2+ ions play a crucial role in stabilizing the three-dimensional (3D) structure of the RNA by stabilizing specific interactions of phosphate groups or phosphate groups and bases of neighboring nucleotides. While many phosphates are accessible to interactions with Mg2+, it is observed that multiple, specific interactions are required to sample conformations close to the folded state; coordination of Mg2+ at individual specific sites facilitates sampling of folded conformations though unfolding ultimately occurs. It is only when multiple specific interactions occur, including the presence of specific inner-shell cation interactions linking two nucleotides, that conformations close to the folded state are stable. While many of the identified Mg2+ interactions are observed in the X-ray crystal structure of Twister, the present study suggests two new Mg2+ ion sites in the Twister ribozyme that contribute to stabilization. In addition, specific interactions with Mg2+ are observed that destabilize the local RNA structure, a process that may facilitate the folding of RNA into its correct structure.

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Contributions and competition of Mg²⁺ and K⁺ in folding and stabilization of the Twister ribozyme.

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OmicsDI is part of the ELIXIR infrastructure

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Dataset Information

Contributions and competition of Mg2+ and K+ in folding and stabilization of the Twister ribozyme.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets

Contributions and competition of Mg²⁺ and K⁺ in folding and stabilization of the Twister ribozyme.