A new study led by Northwestern University unravels the mystery of how RNA molecules fold themselves to fit into cells and perform specific functions. The findings could potentially break a barrier to understanding and developing treatments for RNA-related diseases, including spinal muscle atrophy and perhaps even the novel coronavirus.
“RNA folding is a dynamic process fundamental to life,” said Julius B. Lucks of Northwestern, who led the study. “RNA is a very important part of diagnostic and therapeutic design. The more we know about RNA folding and complexity, the better we can design treatments.”
Using data from RNA folding experiments, the researchers generated the very first data-driven movies on how RNA folds while being made by cellular machines. By watching their videos of this folding, the researchers found that RNA often folds in surprising, perhaps non-intuitive ways, such as tying itself into knots – and then immediately detaching itself to achieve its final structure.
“The folding takes place in your body more than 10 trillion times per second,” said Lucks. “It happens every time a gene is expressed in a cell, but we know so little about it. With our videos, we can finally see folding for the first time.”
The research will be published in the journal Jan. 15 Molecular cell.
Lucks is an associate professor of chemical and biological engineering at McCormick School of Engineering in Northwestern and a member of Northwestern’s Center for Synthetic Biology. He co-led the work with Alan Chen, an associate professor of chemistry at the University of Albany.
While videos of RNA folding do exist, the computer models they generate are full of approximations and assumptions. Lucks’ team has developed a technology platform that captures RNA folding data as the RNA is being made. His group then uses calculation tools to mine and organize the data, revealing points where the RNA folds and what happens after it folds. Angela Yu, a former Lucks student, has fed this data into computer models to generate accurate videos of the folding process.
“The information we provide to the algorithms helps the computer models correct themselves,” said Lucks. “The model makes accurate simulations that are consistent with the data.”
Lucks and his colleagues used this strategy to model the folding of an RNA called SRP, an ancient RNA found in all kingdoms of life. The molecule is known for its distinctive hairpin shape. When watching the videos, the researchers found that the molecule binds itself into a knot and detaches itself very quickly. Then it suddenly snaps into the right hairpin-like structure using an elegant folding path called toehold-mediated strand displacement.
“As far as we know, this has never been seen in nature,” said Lucks. “We think the RNA evolved to detach itself from knots because if knots persist it can render RNA non-functional. The structure is so essential to life that it had to evolve to find a way to get out of it. a knot to come. “
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The study, “Computational reconstruction of RNA cotranscriptional folding pathways from experimental data reveals rearrangement of non-native folding intermediates”, was supported by the National Institutes of Health (award numbers T32GM083937, 1DP2GM110838 and GM120582), the National Science Foundation (award numbers MCB1651877 and 1914567) and the Searle Funds at The Chicago Community Trust.
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