How RNA helped build life’s first proteins

Researchers at University College London have discovered that activated amino acids and sulfur-containing compounds called thiols—both likely present on early Earth—can react in water at neutral pH to form high-energy thioesters. These thioesters transfer the activated amino acids to RNA in a process called RNA aminoacylation, preventing them from joining with free-floating amino acids. These findings suggest that thioesters may have provided the energy needed to unite nucleic acids and amino acids for protein biosynthesis—without the need for enzymes—in Earth’s earliest life-forms.

Proteins are essential to all life on Earth but, unlike nucleic acids such as DNA and RNA, cannot themselves pass specific sequences to their “offspring.”

“This is why life coordinates protein synthesis with another molecule, specifically RNA,” says Matthew W. Powner, lead author of the study (Nature 2025, DOI: 10.1038/s41586-025-09388-y).

In modern cells, enzymes called aminoacyl–transfer RNA (tRNA) synthetases attach amino acids to tRNA, activating them and programming the translation of RNA into proteins. But these enzymes themselves are products of the same genetic code—so how were they made in the first place? “Because you need these proteins to synthesize proteins, it’s a classic chicken-and-the-egg paradox,” Powner says. At life’s origin, these enzymes didn’t exist yet, so the team tried to figure out how amino acids attached to RNA spontaneously in water—the first way life would have had to connect genetic information to functional proteins.

Developing activated amino acids that react selectively with the 2′,3′-hydroxyl (–OH) groups of the ribose sugar of RNA—without enzymes and with other types of molecules that would be present in a cell or the early Earth at the origins of life—has proven challenging. Past attempts have led to hydrolysis or amino acids reacting with themselves. So the team considered the role that thioesters might play in this process.

Thioesters are high-energy compounds that are important in many of life’s biochemical processes and, like RNA aminoacylation, have ancient roots in biochemistry that predate the last universal common ancestor of all life on Earth. In the 1990s, Nobel laureate and biochemist Christian de Duve came up with the “thioester world” hypothesis, which posits that, based on their central role in metabolism, life’s first reactions must have been “powered” by thioesters.

After synthesizing and purifying nucleotides, nucleic acids, and activated amino acids, the team added thioesters to water at neutral pH at varying temperatures from ambient to freezing. They found that the thioesters were surprisingly stable in water, avoiding unwanted peptide formation between amino acids. In the presence of double-stranded RNA structures, thioesters selectively attached amino acids to the 2′,3′-diol groups of the ribose sugar at the 3′ of the double strand, even amid bulk water and excess amines.

The team then tested whether RNA could attach a variety of amino acids in water and found that aminoacylation occurred across all four RNA nucleotides on a broad range of amino acids, including charge residues such as arginine and lysine.

Finally the researchers investigated how these amino acids that were attached to RNA could be used for peptide synthesis under the same plausible prebiotic conditions. They found that when thioesters react with hydrogen sulfide, they form highly reactive thioacids. Those compounds could then be activated to bond with amino acids, even those attached to RNA—switching on peptide synthesis. Ultimately they found that thioesters were selective for aminoacylating RNA, while thioacids enable peptide bond formation, which allows for the stepwise, controlled synthesis of peptides attached to RNA.“A key step missing from prebiotic studies until now has been the use of chemical free energy transfer reactions to overcome the uphill chemistry of assembling polymers in water,” says Charlie Carter, a biochemist and biophysicist at the University of North Carolina School of Medicine who was not involved in this study. “The simplicity of the chemistry used here strongly suggests that it played a significant role in helping to create conditions for life to emerge,” he adds.