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

Elisa Posani, Pavel Janoš, Daniel Haack, Navtej Toor, Massimiliano Bonomi, Alessandra Magistrato () and Giovanni Bussi ()
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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)

Nature Communications, 2025, vol. 16, issue 1, 1-11

Abstract: 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.

Date: 2025
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DOI: 10.1038/s41467-025-59769-0

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