For decades, scientists have chased a mystery about how proteins’ building blocks first hooked up with RNA, the molecule carrying life’s code.
Now, a team of chemists at University College London (UCL) has recreated this elusive step, showing how amino acids could have spontaneously attached to RNA under conditions thought to resemble those on the early Earth.
Amino acids power the machinery of life by forming proteins, while RNA carries the instructions to build them.
Yet how these two vital molecules first found each other has remained unsolved since researchers began probing the origins of life in the 1970s.
Understanding origins of life
“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.
Our study is a big step towards this goal, showing how RNA might have first come to control protein synthesis,” said Matthew Powner, senior author at UCL.
In modern life, protein synthesis depends on an immensely complex molecular machine called the ribosome.
It reads instructions carried in messenger RNA, which delivers a gene’s sequence from DNA to the ribosome.
Acting like a factory assembly line, the ribosome then links amino acids together, one by one, to build a protein.
“We have achieved the first part of that complex process, using very simple chemistry in water at neutral pH to link amino acids to RNA. The chemistry is spontaneous, selective and could have occurred on the early Earth,” Powner added.
Thioesters and early chemistry
Earlier efforts to attach amino acids to RNA had relied on highly reactive compounds that quickly degraded in water and caused amino acids to clump together rather than bind to RNA.
The UCL team instead turned to a gentler activation method inspired by biology. They converted amino acids into a reactive form using thioesters, high-energy compounds vital in many of today’s biochemical processes and long hypothesized to have powered life’s first reactions.
Powner noted that the findings unite two leading origin-of-life ideas: the “RNA world,” where RNA was the key self-replicator, and the “thioester world,” in which thioesters provided the energy for primitive metabolism.
To make thioesters, amino acids were reacted with pantetheine, a sulfur-bearing molecule that the same group previously showed could form under early Earth-like conditions.
That work suggested pantetheine may have been available in primordial ponds or lakes, providing the raw chemistry needed to kickstart life.
The researchers say the next challenge is understanding how RNA could begin binding specific amino acids consistently, laying the foundation for the genetic code.
“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,” said Powner.
Building life’s LEGO pieces
Lead author Dr. Jyoti Singh likened the work to building with molecular LEGO bricks.
“Imagine the day that chemists might take simple, small molecules, consisting of carbon, nitrogen, hydrogen, oxygen, and sulphur atoms, and from these LEGO pieces form molecules capable of self-replication. This would be a monumental step towards solving the question of life’s origin,” she said.
The study showed that once amino acids were loaded onto RNA, they could link together to form peptides, the short chains of amino acids essential to life. Crucially, the activated amino acid used was a thioester derived from Coenzyme A, a molecule found in all living cells today. This discovery, the researchers suggest, could help connect early metabolism with the emergence of the genetic code and protein building.
While the study focused on chemistry alone, the team believes such reactions were most likely to occur in shallow pools or lakes, where molecules could concentrate enough to interact.
They tracked the microscopic reactions using advanced tools such as magnetic resonance imaging, which reveals atomic structures, and mass spectrometry, which identifies molecular sizes.
The research was supported by the Engineering and Physical Sciences Research Council (EPSRC), the Simons Foundation, and the Royal Society.
The findings have been published in the journal Nature.
