Similar to a light switch, RNA switches (called riboswitches) determine which genes turn “on” and “off.” Although this may seem like a simple process, the inner workings of these switches have confounded biologists for decades.
Now researchers led by Northwestern University and the University at Albany discovered one part of RNA smoothly invades and displaces another part of the same RNA, enabling the structure to rapidly and dramatically change shape. Called “strand displacement,” this mechanism appears to switch genetic expression from “on” to “off.”
Using a simulation they launched last year, the researchers made this discovery by watching a slow-motion simulation of a riboswitch up close and in action. Affectionately called R2D2 (short for “reconstructing RNA dynamics from data”), the new simulation models RNA in three dimensions as it binds to a compound, communicates along its length and folds to turn a gene “on” or “off.”
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“We have found this strand displacement mechanism occurring in other types of RNA molecules, indicating this might be a potential generality of RNA folding,” said Northwestern’s Julius B. Lucks, who co-led the study. “We are starting to find similarities among different types of RNA molecules, which could eventually lead to RNA design rules for folding and function.”
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Although RNA folding takes place in the human body more than 10 quadrillion times per second—every time a gene is expressed in a cell—researchers know very little about the process. To help visualize and understand the mysterious yet crucial process, Lucks and Chen unveiled R2D2 last year, in a paper published in the journal Molecular Cell.
Credit: Northwestern University
Employing a technology platform developed in Lucks’ lab, R2D2 captures data related to RNA folding as the RNA is being made. Then, it uses computational tools to mine and organize the data, revealing points where the RNA folds and what happens after it folds. Angela Yu, a former student of Lucks, inputted this data into computer models to generate accurate videos of the folding process.
“What’s so groundbreaking about the R2D2 approach…is that it combines experimental data on RNA folding at the nucleotide level with predictive algorithms at the atomic level to simulate RNA folding in ultra-slow motion,” said Dr. Francis Collins, director of the National Institutes of Health, in his February 2021 blog. “While other computer simulations have been available for decades, they have lacked much-needed experimental data of this complex folding process to confirm their mathematical modeling.”
