{"id":323338,"date":"2025-12-02T19:10:07","date_gmt":"2025-12-02T19:10:07","guid":{"rendered":"https:\/\/www.newsbeep.com\/au\/323338\/"},"modified":"2025-12-02T19:10:07","modified_gmt":"2025-12-02T19:10:07","slug":"visualizing-ribozyme-assembly-with-cryo-em","status":"publish","type":"post","link":"https:\/\/www.newsbeep.com\/au\/323338\/","title":{"rendered":"Visualizing Ribozyme Assembly With Cryo-EM"},"content":{"rendered":"

Original story from the European Molecular Biology Laboratory (EMBL; Grenoble, France).<\/a><\/p>\n

Researchers have visualized how a large RNA molecule assembles itself into a functional machine.<\/p>\n

RNA is a central biological macromolecule, now widely harnessed in medicine and nanotechnology. Like proteins, RNA function often depends on its precise 3D structure. A recent study led by Marco Marcia \u2013 former EMBL Grenoble<\/a> (France) Group Leader and current Associate Professor and SciLifeLab Group leader at Uppsala University<\/a> (Sweden) \u2013 has captured, for the first time, a ribozyme in motion \u2013 almost frame by frame. The researchers recorded how this tiny RNA machine folds, flexes and assembles itself, revealing its intricate choreography in unprecedented detail.<\/p>\n

Using an integrative structural biology approach combining state-of-the-art techniques \u2013 cryogenic electron microscopy (cryo-EM), small-angle X-ray scattering (SAXS), RNA biochemistry and enzymology, image processing and molecular simulations \u2013 the scientists observed the assembly of a self-splicing ribozyme, which is an RNA molecule that can \u2018cut and paste\u2019 its own sequence, essentially editing itself to become operational. They captured the dynamic \u2018behind-the-scenes\u2019 process by which the self-splicing ribozyme folds into its functional structure.<\/p>\n

This breakthrough was made possible thanks to the cutting-edge facilities and expert services at EMBL Grenoble, which enabled the integration of advanced structural biology methods with RNA biochemistry and enzymology. The Marcia group also benefited from close collaboration with the Centre for Structural Systems Biology (CSSB) Hamburg<\/a> (Germany), where innovative cryo-EM image processing approaches tailored for this specific project were developed, and the Istituto Italiano di Tecnologia<\/a> (IIT; Genoa, Italy), which provided high-level molecular simulation expertise.<\/p>\n

\u201cDetermining RNA structures is a challenging task \u2013 the inherent flexibility and negative charge make RNA a notoriously difficult target for structural studies,\u201d shared Shekhar Jadhav, former predoctoral Fellow at EMBL Grenoble, now a postdoc at Uppsala University. \u201cPersistent efforts and extensive screening on electron microscopes ultimately led us to visualize elusive RNA dynamics.\u201d<\/p>\n

The result is the most complete \u2018molecular film\u2019 to date of an RNA molecule building itself, revealing how it avoids the biological equivalent of outtakes: misfolded, non-functional states known as kinetic traps.<\/p>\n

How one domain orchestrates the RNA storyline<\/p>\n

At the heart of this production is Domain 1 (D1), the ribozyme\u2019s central scaffold and, as it turns out, its director. This domain acts as a molecular gate, cueing the other domains (D2, D3, D4) to enter at precisely the right moment during the folding process.<\/p>\n

Subtle movements in key parts of the D1 molecule prompt one of its sections to open up and make way for the next. Each domain joins the scene only when the previous one is correctly in place, creating a seamless sequence of molecular choreography that prevents structural errors and ensures a flawless finale: the formation of a structure that can catalyze a chemical reaction, essential to the ribozyme\u2019s function.<\/p>\n

\"\"Cryo-EM captures the protein that recruits its own bodyguards<\/a><\/p>\n

Research captures how the GRP94 protein shields itself to make sure it forms properly and suggests a way to target it for future disease treatments.<\/p>\n

Capturing the hidden takes<\/p>\n

By analyzing hundreds of thousands of single RNA molecules, the team reconstructed intermediate \u2018takes\u2019 that were invisible in static crystal structures. These fleeting frames show how the RNA explores alternative poses before settling into its final conformation.<\/p>\n

\u201cTo capture these fleeting frames, we had to develop novel cryo-EM image-processing strategies,\u201d explained Maya Topf, Group Leader at CSSB and a collaborator on the study. \u201cThis is a great example of how computational innovation and high-quality cryo-EM data can reveal the hidden conformations of molecular machines.\u201d<\/p>\n

SAXS data and molecular dynamics simulations offered complementary insight into conformational plasticity, helping the scientists refine each structural frame and assemble the full storyline. The researchers found that the energy needed by the ribozyme to shift between different shapes was very small, which not only allows the RNA to move smoothly from one form to another in real life, but also makes it easier for computers to accurately simulate these natural transitions without the molecule getting stuck in unrealistic positions.<\/p>\n

\u201cOne major strength of this work is the synergy between these cutting-edge new structural data on RNA and our advanced molecular simulations of this challenging system,\u201d commented Marco De Vivo, Head of Molecular Modeling and Drug Discovery Lab and Associate Director for Computation at IIT, and one of the collaborators on this study. \u201cThis combined approach has clarified, at an unprecedented atomistic level of detail, the dynamic that drives the entire assembly of this RNA molecule, which now opens new avenues for drug discovery efforts targeting RNA.\u201d<\/p>\n

From ancient scripts to modern spin-offs<\/p>\n

Group II introns, the ribozymes featured in this molecular film, are thought to be the ancestors of the spliceosome, the complex machinery that edits RNA in human cells.<\/p>\n

By revealing how these molecules fold efficiently and avoid kinetic traps, the study provides a new insight into how early RNA-based life may have evolved its RNA editing tools. Beyond evolutionary lore, this work also sets the stage for RNA design and engineering \u2013 guiding how future biotechnologies might script RNA molecules to fold correctly for use in therapeutics or nanobiotechnology.<\/p>\n

Opening the door to RNA AI<\/p>\n

The detailed datasets and molecular mechanisms uncovered in this study offer a valuable benchmark for training and testing AI models. Some of the RNA structures resolved here have already been used in international CASP<\/a> competitions \u2013 the same predictive challenge that gave rise to AlphaFold.<\/p>\n

\u201cThis work is expected to play a key role in shaping artificial intelligence approaches to RNA structure prediction, paving the way towards a new \u2018AlphaFold for RNA\u2019,\u201d concluded Marcia.<\/p>\n

This convergence of experimental precision and machine learning marks a new phase for RNA structural biology, where AI and cryo-EM and complementary experimental approaches can learn from each other to predict, visualize and understand the dynamics of life\u2019s most versatile molecule.<\/p>\n

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