BUFFALO, N.Y. — Before the first cells enclosed chemistry inside membranes, life faced a basic logistical problem: molecules needed to find one another in a hostile, watery environment. RNA may have offered an answer. A new study led by researchers at the University at Buffalo suggests that a minute chemical difference between RNA and DNA can determine whether these molecules remain dispersed, gather into liquid-like droplets or become trapped in gel-like networks. The finding adds a new layer to the RNA world hypothesis, which proposes that RNA may have served as both genetic material and a catalyst for chemical reactions during the earliest stages of life. By showing how one oxygen-containing chemical group influences the formation and physical behavior of RNA condensates, the researchers have identified a molecular switch that may have helped primitive biochemical systems organize themselves before the evolution of true cells.
The study, published in Nature Communications, focuses on biomolecular condensates: concentrated, membrane-free compartments formed when molecules separate from their surroundings in a process known as liquid-liquid phase separation. Unlike conventional organelles, condensates do not require a surrounding lipid membrane. Instead, weak and reversible interactions among molecules cause them to cluster into droplets, much like oil separating from water. In modern cells, comparable condensates help organize processes such as gene regulation, RNA processing and cellular stress responses. Under prebiotic conditions, RNA droplets could have concentrated otherwise dilute molecules, increasing the chances that RNA strands would interact, copy information or participate in chemical reactions. They may also have reduced exposure to damaging environmental conditions, including heat, acidity and fluctuating concentrations of salts and minerals.
The new work builds on earlier research from the Banerjee laboratory showing that RNA can assemble into liquid-like droplets at elevated temperatures. In the latest experiments, the team compared RNA with single-stranded DNA molecules designed to contain essentially the same sequences. The comparison allowed the researchers to isolate the influence of chemical structure rather than differences in genetic information. RNA began forming condensates at temperatures approximately 10 degrees Celsius lower than the corresponding DNA. That result indicates that RNA has a stronger intrinsic tendency to condense as temperature rises. The researchers also observed an important difference in the internal organization of the droplets. RNA was more likely than DNA to form interconnected molecular networks, causing the condensates to shift from relatively fluid materials toward more elastic, gel-like states.
The contrast between the two nucleic acids is striking because RNA and DNA are chemically similar. Both are built from repeating nucleotide units, each containing a sugar, a phosphate group and a nitrogen-containing base. The critical distinction lies in the sugar. RNA contains ribose, whose 2′ carbon carries a hydroxyl group made of oxygen and hydrogen. DNA contains deoxyribose, which lacks that oxygen-containing 2′-hydroxyl, or 2′-OH, group. This apparently modest change alters how the nucleic-acid backbone interacts with its surroundings. According to the study, the 2′-OH helps RNA interact more strongly with magnesium ions and changes the hydration shell surrounding the molecule. RNA retains fewer water molecules around its backbone than the comparable DNA, making RNA strands more likely to approach one another and participate in the interactions needed for condensation.
Magnesium appears to be especially important because positively charged ions can partially offset the negative charges carried by the phosphate groups in RNA and DNA. Without this charge screening, neighboring nucleic-acid strands repel one another strongly. Magnesium reduces that electrostatic barrier, allowing the polymers to come closer. The researchers’ temperature-controlled microscopy experiments showed how these molecular interactions changed as the samples were heated. They supplemented the imaging with small-angle X-ray scattering, a technique that reveals the nanoscale arrangement of molecules, and molecular-dynamics simulations carried out by collaborators at Princeton University. Together, the approaches linked the visible emergence of droplets to changes in hydration, ion coordination and the organization of RNA chains at microscopic scales.
The researchers then performed a chemical test of the proposed mechanism by modifying the 2′-OH group. They replaced it with a 2′-O-methyl group, a modification found in many naturally occurring RNA molecules and widely used to alter RNA stability and behavior. The modified RNA showed a weaker tendency to condense, and its resulting materials displayed different physical properties. In particular, changing the group affected whether the condensates remained dynamic and fluid or developed interconnected, gel-like structures. The experiment strengthened the conclusion that the 2′-OH is not merely a passive chemical feature. It actively influences how RNA molecules bind ions, organize water and establish the network of contacts that governs a condensate’s transition from a droplet to a more arrested material.
That transition could have mattered during the origin of life. A liquid condensate can continuously exchange molecules with its surroundings, allowing reactions and molecular rearrangements to proceed. A gel-like network, by contrast, can hold RNA strands in place for longer periods and may provide greater physical protection. The two states could therefore offer different advantages: fluid droplets might support rapid interactions and chemical activity, while more rigid networks could preserve vulnerable molecules during environmental stress. The researchers are not claiming that modern RNA droplets were themselves the first cells, nor that condensates alone solve every problem posed by the RNA world. Instead, the findings suggest that RNA possessed chemical properties capable of producing organized compartments without membranes, potentially creating intermediate environments between freely dispersed molecules and fully developed cellular life.
The Banerjee laboratory is now investigating whether RNA condensates can be engineered to carry out basic cell-like functions, including biochemical reactions. The long-term goal is to create active, dynamic, cell-sized compartments made primarily or entirely from RNA. Such systems could help scientists explore how molecular networks became organized before biological membranes, proteins and complex genomes emerged. They may also contribute to the design of synthetic cells and programmable biomolecular materials. The study’s central message is that large-scale biological organization can arise from a very small molecular distinction. One hydroxyl group can alter ion binding, water structure, phase separation and the mechanical state of an entire condensate. If similar RNA compartments existed on the early Earth, their ability to concentrate, protect and organize molecules may have helped bridge the enormous gap between chemistry and the first cellular systems.
Subject of Research: RNA condensates, phase separation, and the molecular origins of cellular organization
Article Title: The role of the 2’-OH group in phase separation and percolation transitions of RNA
News Publication Date: 31 July 2026
Web References: https://www.nature.com/articles/s41467-026-75961-2
References: Nature Communications; DOI: 10.1038/s41467-026-75961-2
Image Credits: Priya Banerjee/University at Buffalo
Keywords
RNA condensates, RNA droplets, DNA, 2′-hydroxyl group, phase separation, liquid-liquid phase separation, RNA world hypothesis, origin of life, biomolecular condensates, magnesium ions, molecular dynamics, synthetic cells, prebiotic chemistry, gel-like networks
