Ancient ‘folding’ proteins help unravel the mystery of the origin of life

How did life start from nothing?

Even though the primordial Earth had hundreds of amino acids, all living things use the same 20 of these compounds. Science has struggled to pinpoint what's so special—if anything—about those 20 'canonical' amino acids. 

"We're trying to find out what was so special about our canonical amino acids," said co-author Stephen Fried in a press release who is a chemist at Johns Hopkins University. "Were they selected for any particular reason?"

By combining a set of amino acids that were particularly abundant before life first appeared on Earth, the researchers could recreate the synthesis of proteins 4 billion years ago in the lab. 

Some amino acids are thought to have come from meteorites that struck the planet more frequently than they do now. Others may have been created when ultraviolet (UV) light from the Sun reacted with molecules in the atmosphere of the time.

The team's investigations revealed that a form of natural selection was occurring even in the absence of life. 

Significantly, the amino acids most adapted for 'folding proteins' into shapes essential to vital functions tend to be integrated into the biochemistry of ancient organic compounds. In this way, such compounds had a better chance of survival. Over time, more chemical molecules with these favorable characteristics for life emerged.

“To have evolution in the Darwinian sense, you need to have this whole sophisticated way of turning genetic molecules like DNA and RNA into proteins,” said Fried. 

“But replicating DNA also requires proteins, so we have a chicken-and-egg problem. Our research shows that nature could have selected for building blocks with useful properties before Darwinian evolution.”

Amino acids have been discovered in asteroids distant from Earth, indicating that these substances are common across the universe. Fried believes the new findings may also impact the likelihood of discovering extraterrestrial life.

The full study was published in the Journal of the American Chemical Society on February 24 and can be found here.

Study abstract:

Whereas modern proteins rely on a quasi-universal repertoire of 20 canonical amino acids (AAs), numerous lines of evidence suggest that ancient proteins relied on a limited alphabet of 10 “early” AAs and that the 10 “late” AAs were products of biosynthetic pathways. However, many nonproteinogenic AAs were also prebiotically available, which begs two fundamental questions: Why do we have the current modern amino acid alphabet and would proteins be able to fold into globular structures as well if different amino acids comprised the genetic code? Here, we experimentally evaluate the solubility and secondary structure propensities of several prebiotically relevant amino acids in the context of synthetic combinatorial 25-mer peptide libraries. The most prebiotically abundant linear aliphatic and basic residues were incorporated along with or in place of other early amino acids to explore these alternative sequence spaces. The results show that foldability was likely a critical factor in the selection of the canonical alphabet. Unbranched aliphatic amino acids were purged from the proteinogenic alphabet despite their high prebiotic abundance because they generate polypeptides that are over solubilized and have low packing efficiency. Surprisingly, we find that the inclusion of a short-chain basic amino acid also decreases polypeptides’ secondary structure potential, for which we suggest a biophysical model. Our results support the view that, despite lacking basic residues, the early canonical alphabet was remarkably adaptive at supporting protein folding and explain why basic residues were only incorporated at a later stage of protein evolution.