The stability of alpha amino acids may explain their role as the protein building blocks of early life

A new study from the Hebrew University of Jerusalem published in the Proceedings of the National Academy of Sciences sheds light on one of life’s greatest mysteries: why biology is based on a very specific set of amino acids and, in particular, why nature selected alpha amino acids as the basis for proteins.

The research, led by Dr. Moran Frenkel-Pinter and her laboratory, Sarah Fisher and Yishi Ezerzer, from the Institute of Chemistry and the Center for Nanoscience and Nanotechnology at the Hebrew University, explored the properties of depsipeptides, simple peptide molecules that could have formed on the early Earth through natural processes.

Unlike modern peptides, depsipeptides contain a mixture of ester and amide bonds, making them easier to form under prebiotic conditions but less stable over time.

Every living organism on Earth makes its proteins from the same set of 20 amino acids. Why that specific set? The new study suggests that life’s dependence on these 20 amino acids is no accident. A key question has puzzled scientists for decades: Why did life favor alpha amino acids over their beta or gamma counterparts, even though they were all abundant on prebiotic earth?

To test whether molecular assembly played a role, Frenkel-Pinter and his team synthesized depsipeptides using a wide range of hydroxy and amino acids, then looked at their ability to self-assemble in solution.

The results were surprising. Depsipeptides constructed from alpha acids readily formed stable droplet-like assemblies that persisted for weeks, even after freezing and thawing. In contrast, beta-based assemblies, if formed, separated more quickly in solution and showed significantly lower physical stability. This difference, the researchers argue, could have been a decisive factor in the evolutionary “choice” of the alpha spine.

“Self-assembly is one of the most fundamental prerequisites of life,” said Dr. Frenkel-Pinter. “Our findings suggest that the superior ability of alpha-based proto-peptides to form stable compartments may have given them a crucial evolutionary edge, setting the stage for the protein trunks we see in biology today.”

“The question of why Evolution selected a specific set of amino acids has long remained a mystery. Taking even a single step toward answering this long-standing question is remarkable, and it is a privilege to contribute to this search,” said Ezerzer, a student teacher co-authoring this project with Fisher.

“We demonstrate here, for the first time, the ability of depsipeptides to self-assemble, similar to modern peptides. While these findings are a breakthrough in the field of chemical evolution, they may also have future implications for other fields such as the pharmaceutical industry,” Fisher said.

The study marks the first time that the assembly properties of alpha backbonds and beta protopeptide have been directly compared. By showing that stability at the molecular level could have influenced chemical evolution, the research proposes an assembly-driven selection model for the first building blocks of life.

These findings add a new dimension to origins of life studies, suggesting that it was not just chemical reactivity but also the capacity for long-lived self-assembly that shaped the transition from prebiotic chemistry to biology.