RNA and Sulfur Compounds Possibly Created the First Peptides on Earth

Long before dinosaurs munched on leafy greens or photosynthesizing algae soaked up the sun, a lifeless soup of simple molecules floated through the watery and rocky landscape of early planet Earth. Today, complex molecular processes in cells create the building blocks of life: proteins, lipids, and more. But how did life emerge before these systems evolved?

Now, scientists have discovered chemical reactions that could have allowed the very first peptides to form under the Earth’s conditions about four billion years ago.¹ They published their results in Nature.

“Life relies on the ability to synthesize proteins—they are life’s key functional molecules. Understanding the origin of protein synthesis is fundamental to understanding where life came from,” said Matthew Powner, a chemist at University College London and senior author of the new study, in a press release.

In modern times, the first step of creating a protein requires transfer RNAs (tRNAs) to become aminoacylated or “charged” with an amino acid. As ribosomes read the mRNA transcript, tRNAs with amino acids complementary to the mRNA sequence get added to the growing peptide chain that will eventually fold into a protein.

Aminoacylation occurs with the help of energy in the form of ATP and an aminoacyl-tRNA synthetase enzyme. In a classic chicken-and-egg problem, these synthetase enzymes are proteins themselves and must have been made by ribosomes. So, Powner and his team set out to see if they could find a chemical—not biological—process that could allow tRNAs to become charged with an amino acid.

Scientists speculate that life on Earth could have come from self-replicating RNA molecules, called the “RNA world” hypothesis, or that it arose from metabolism driven by high energy sulfur-containing compounds in the “thioester world” theory.

The researchers found that amino acids could react with a sulfur-containing compound to form aminoacyl-thiols. When the team mixed an aminoacyl-thiol with RNA in water and at a neutral pH, the reaction led to an aminoacylated RNA.

Normally, amino acids get added to the 3’ end of the tRNA molecule, and the researchers saw that when they only used single-stranded RNA in their reaction, aminoacylation occurred in different locations along the molecule. However, if they added double-stranded RNA to the reaction—which is more similar to the actual tRNA structure—they saw that the amino acid was added to the 3’ end of the RNA.

To continue translation, new tRNAs loaded with amino acids must add the new amino acid to the growing peptide chain. The team showed that if they added an aminothioacid molecule, which carried a new amino acid, in the presence of an oxidizing agent, that new amino acid formed a peptide bond with the amino acid on the aminoacylated RNA. Arup Dalal and Sheref Mansy, chemists at the University of Trento who were not involved in the research but who wrote an accompanying News and Views article about the study, were particularly impressed that Powner and his team showed that both the tRNA aminoacylation step and the peptide synthesis step could occur in the same reaction tube. This finding lends even more support to the hypothesis that this process could have led to the first peptide synthesis.

Additional research will be needed to see how this process or a similar one could lead to sequence specificity—how certain RNA sequences became matched with specific amino acids. “There are numerous problems to overcome before we can fully elucidate the origin of life, but the most challenging and exciting remains the origins of protein synthesis,” Powner said.