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 foundation for proteins.
The research, led by Dr. Moran Frenkel-Pinter and her lab members Sarah Fisher and Yishi Ezerzer of the Institute of Chemistry and the Center for Nanoscience and Nanotechnology at the Hebrew University, explored the properties of depsipeptides—simple model peptide-like molecules that could have formed on early Earth through natural processes.
Unlike modern peptides, depsipeptides contain a mix of ester and amide bonds, making them easier to form under prebiotic conditions but less stable over time.
Every living organism on Earth forms its proteins from the exact 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 all were abundant on prebiotic Earth?
To test whether molecular assembly played a role, Frenkel-Pinter and her team synthesized depsipeptides using a wide range of hydroxy and amino acids, then observed their ability to self-assemble in solution.
The results were striking. Depsipeptides built 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, phase-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 backbone.
“Self-assembly is one of life’s most fundamental prerequisites,” 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 backbones we see in biology today.”
“The question of why evolution handpicked a specific set of amino acids has remained a mystery for a very long time. Taking even a single step toward answering this long-lasting question is remarkable, and it is a privilege to contribute to this pursuit,” said Ezerzer, a master’s student co-leading this project together 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,” said Fisher.
The study marks the first time that the assembly properties of alpha and beta proto-peptide backbones have been directly compared. By demonstrating that stability at the molecular level could have influenced chemical evolution, the research proposes an assembly-driven selection model for life’s earliest building blocks.
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-lasting self-assembly that shaped the transition from prebiotic chemistry to biology.
More information: Proto-peptide Backbone Affects Assembly in Aqueous Solutions, Proceedings of the National Academy of Sciences (2025). www.pnas.org/doi/10.1073/pnas.2500503122
Journal information: Proceedings of the National Academy of Sciences
Provided by Hebrew University of Jerusalem
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