A tiny chemical difference makes RNA better than DNA at forming liquid-like droplets under high temperatures and acidic conditions.
One of the biggest puzzles in origin of life research comes before the first cells even existed: How could RNA molecules gather in one place, interact, and help produce early life without cellular compartments to hold them together?
Without those boundaries, fragile RNA molecules would have struggled to encounter one another often enough in the primordial soup, while also surviving the hot and acidic conditions thought to characterize early Earth.
One possible solution is RNA’s ability to collect into liquid-like droplets known as condensates. These structures have no membrane, but they could have concentrated RNA molecules in small spaces, giving them more opportunities to interact while potentially offering some protection from harsh surroundings.
Research led by the University at Buffalo is now helping explain why RNA is especially capable of forming these droplets. Published in Nature Communications, the study found that a very small chemical distinction between RNA and DNA helps RNA assemble into droplets more readily as temperatures increase. That same difference also makes the droplets more likely to develop into rigid, gel-like networks.
“These findings reveal, for the first time, how remarkably small changes in molecular chemistry can control the emergence of much larger, self-organized biomolecular structures like RNA condensates,” says lead corresponding author Priya R. Banerjee, PhD, Twentieth Century Club Professor in the UB Department of Physics. “They could allow us to eventually address even deeper questions, like whether these condensates helped bridge the gap between simple molecules and the earliest forms of life.”
The research was conducted with Jerelle Joseph, PhD, assistant professor of chemical and biological engineering at Princeton University, and received support from the National Institutes of Health, the National Science Foundation, and Hypothesis Fund.
RNA droplets could solve a prebiotic problem
The study is part of Banerjee’s broader work on RNA world theory, which proposes that RNA was central to the emergence of life on Earth. Because RNA can both store genetic information and catalyze chemical reactions, it may have been capable of carrying out chemistry that eventually contributed to the emergence of DNA, proteins, and the first cells.
A major challenge for the theory is explaining how relatively unstable RNA could have endured harsh prebiotic environments and how enough molecules could have accumulated together to interact before cellular compartments existed.
Heat transforms clusters of RNA into liquid-like droplets. The study found that temperature can alter the physical properties of RNA condensates, allowing a more networked structure to relax into rounded droplets. Credit: Priya Banerjee/University at Buffalo
RNA condensates may offer part of the explanation. In a 2023 study, Banerjee and colleagues showed that RNA naturally tends to organize into liquid-like droplets at high temperatures.
The researchers built on that finding by directly comparing RNA with single-stranded DNA containing essentially the same sequences.
Their experiments showed that RNA started forming droplets at temperatures about 10 degrees Celsius lower than comparable DNA, indicating that RNA has a stronger tendency to condense. RNA also formed interconnected networks within the droplets more easily, shifting the material from a fluid state toward a more gel-like structure that could offer greater protection under harsh environmental conditions.
One oxygen atom changes condensation
The difference appears to stem partly from a remarkably small chemical distinction. RNA and DNA differ by only one oxygen atom on each sugar unit. RNA contains a chemical group called a 2′-hydroxyl (2′-OH), which DNA lacks.
Using temperature-controlled microscopy, small-angle X-ray scattering, and molecular dynamics simulations carried out by the Joseph group, the researchers found that the 2′-OH appears to strengthen RNA’s interactions with magnesium ions while reducing the number of water molecules surrounding its backbone compared with DNA. Together, those properties make it easier for RNA molecules to gather as temperature rises.
To test whether the 2′-OH was responsible, the researchers chemically altered it to 2′-Ome, a modification similar to those present in many naturally occurring RNA molecules. The change reduced RNA’s tendency to condense and affected whether the resulting droplets stayed fluid or developed into gel-like material.
“This single oxygen-containing group on RNA’s sugar has a surprisingly powerful effect on whether these molecules come together, remain dynamic or become arrested into a gel-like material,” says first author Gable Wadsworth, PhD, a postdoc in Banerjee’s lab who will join the University of Texas at El Paso as an assistant professor this fall.
Researchers are building cell-sized RNA compartments
Banerjee’s laboratory is now trying to engineer RNA droplets capable of performing some basic cellular functions, including biochemical reactions. The researchers hope to program them as active, dynamic, cell-sized compartments that could eventually provide a foundation for creating synthetic cells made entirely from RNA.
“These kinds of self-organizing RNA compartments were possibly a step along the way to single-cell organisms,” Banerjee says.
Reference: “The role of the 2’-OH group in phase separation and percolation transitions of RNA” by Gable M. Wadsworth, Dilimulati Aierken, George M. Thurston, Jerelle A. Joseph and Priya R. Banerjee, 31 July 2026, Nature Communications.
DOI: 10.1038/s41467-026-75961-2
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