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Ensemble refinement of mismodeled cryo-EM RNA structures using all-atom simulations

Author

Listed:
  • Elisa Posani

    (Scuola Internazionale Superiore di Studi Avanzati (SISSA))

  • Pavel Janoš

    (CNR-IOM at SISSA)

  • Daniel Haack

    (University of California, San Diego)

  • Navtej Toor

    (University of California, San Diego)

  • Massimiliano Bonomi

    (Institut Pasteur, Université Paris Cité, CNRS UMR 3528, Computational Structural Biology Unit)

  • Alessandra Magistrato

    (CNR-IOM at SISSA)

  • Giovanni Bussi

    (Scuola Internazionale Superiore di Studi Avanzati (SISSA))

Abstract

The advent of single-particle cryogenic electron microscopy (cryo-EM) has enabled near-atomic resolution imaging of large macromolecules, enhancing functional insights. However, current cryo-EM refinement tools condense all single-particle images into a single structure, which can misrepresent highly flexible molecules like RNAs. Here, we combine molecular dynamics simulations with cryo-EM density maps to better account for the structural dynamics of a complex and biologically relevant RNA macromolecule. Namely, using metainference, a Bayesian method, we reconstruct an ensemble of structures of the group II intron ribozyme, which better matches experimental data, and we reveal inaccuracies of single-structure approaches in modeling flexible regions. An analysis of all RNA-containing structures deposited in the Protein Data Bank reveals that this issue affects most cryo-EM structures in the 2.5–4 Å range. Thus, RNA structures determined by cryo-EM require careful handling, and our method may be broadly applicable to other RNA systems.

Suggested Citation

  • Elisa Posani & Pavel Janoš & Daniel Haack & Navtej Toor & Massimiliano Bonomi & Alessandra Magistrato & Giovanni Bussi, 2025. "Ensemble refinement of mismodeled cryo-EM RNA structures using all-atom simulations," Nature Communications, Nature, vol. 16(1), pages 1-11, December.
  • Handle: RePEc:nat:natcom:v:16:y:2025:i:1:d:10.1038_s41467-025-59769-0
    DOI: 10.1038/s41467-025-59769-0
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