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Mg²⁺ Impacts the Twister Ribozyme through Push-Pull Stabilization of Nonsequential Phosphate Pairs.

ABSTRACT: RNA molecules perform a variety of biological functions for which the correct three-dimensional structure is essential, including as ribozymes where they catalyze chemical reactions. Metal ions, especially Mg²⁺, neutralize these negatively charged nucleic acids and specifically stabilize RNA tertiary structures as well as impact the folding landscape of RNAs as they assume their tertiary structures. Specific binding sites of Mg²⁺ in folded conformations of RNA have been studied extensively; however, the full range of interactions of the ion with compact intermediates and unfolded states of RNA is challenging to investigate, and the atomic details of the mechanism by which the ion facilitates tertiary structure formation is not fully known. Here, umbrella sampling combined with oscillating chemical potential Grand Canonical Monte Carlo/molecular dynamics simulations are used to capture the energetics and atomic-level details of Mg²⁺-RNA interactions that occur along an unfolding pathway of the Twister ribozyme. The free energy profiles reveal stabilization of partially unfolded states by Mg²⁺, as observed in unfolding experiments, with this stabilization being due to increased sampling of simultaneous interactions of Mg²⁺ with two or more nonsequential phosphate groups. Notably, these results indicate a push-pull mechanism in which the Mg²⁺-RNA interactions actually lead to destabilization of specific nonsequential phosphate-phosphate interactions (i.e., pushed apart), whereas other interactions are stabilized (i.e., pulled together), a balance that stabilizes unfolded states and facilitates the folding of Twister, including the formation of hydrogen bonds associated with the tertiary structure. This study establishes a better understanding of how Mg²⁺-ion interactions contribute to RNA structural properties and stability.

SUBMITTER: Kognole AA

PROVIDER: S-EPMC7091459 | 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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Mg²⁺ Impacts the Twister Ribozyme through Push-Pull Stabilization of Nonsequential Phosphate Pairs.

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OmicsDI is part of the ELIXIR infrastructure

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Dataset Information

Mg2+ Impacts the Twister Ribozyme through Push-Pull Stabilization of Nonsequential Phosphate Pairs.

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OmicsDI is part of the ELIXIR infrastructure

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Mg²⁺ Impacts the Twister Ribozyme through Push-Pull Stabilization of Nonsequential Phosphate Pairs.