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Poster De Conférence Année : 2022

Exploring the Role of Divalent Cations in the Hammerhead Ribozyme Mechanism with Molecular Simulations

Résumé

RNA enzymes, called ribozymes, are found to be involved in an increasing number of biological processes. An intriguing question pertains to the role played by divalent cations in the ribozyme activity; for the hammerhead ribozyme, the cleavage reaction is 500 times faster in the presence of Mg2+ than in the presence of Ca2+ and 10 000 times faster than in the presence of Na+. We face several challenges: first, the interaction of divalent ions with negatively charged nucleic acids is notoriously poorly described in standard classical simulations due to an oversimplified description of electrostatic interactions, making it difficult to properly capture their slow reorganization along the reaction; here, we thus examine how different strategies to include electronic polarization effects in force fields —implicitly through the use of scaled charges or pair-specific Lennard-Jones parameters, or explicitly with polarizable force fields, the Drude polarizable force field and AMOEBA — capture the interaction of a model phosphate compound, dimethylphosphate. We show that the computational efficiency of implicit models makes them ideally suited for large-scale simulations of biological assemblies, with improved accuracy compared to state-of-the-art fixed-charge force fields. Since RNA is very flexible, it is necessary to properly sample their conformations with the use of specific tools (REST2) to characterize the conformational fluctuations of the active site in the presence of different cations.From the main identified conformations, the Adaptive String Method with a QM(DFTB3)/MM MD description is used in order to study the reaction mechanism.
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Dates et versions

hal-04476086 , version 1 (24-02-2024)

Identifiants

  • HAL Id : hal-04476086 , version 1

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Julie Puyo-Fourtine, Marie Juillé, Jérôme Hénin, Carine Clavaguéra, Iñaki Tuñon, et al.. Exploring the Role of Divalent Cations in the Hammerhead Ribozyme Mechanism with Molecular Simulations. Molecular Simulation 2022: Present, Past and Future, Jun 2022, Erice (Sicile), Italy. ⟨hal-04476086⟩
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