# Protopeptide backbone affects assembly in aqueous solutions

## TL;DR

The paper explores how the structure of early peptides may have influenced their assembly in water, potentially explaining why certain amino acids became central to life.

## Contribution

The study introduces an assembly-driven model for the selection of alpha amino acids in early life through depsipeptide experiments.

## Key findings

- Depsipeptides with alpha hydroxy acid backbones form more stable assemblies than beta analogs in aqueous solutions.
- Hydrophobic hydroxy acids in depsipeptide systems promote assembly formation.
- Assembly stability may have guided the selection of alpha amino acids in early biochemical evolution.

## Abstract

The question of how the protein backbone was selected during early chemical evolution remains one of the most fascinating and puzzling mysteries in origins-of-life research. In this paper, we investigate how the chemical and physical properties of primordial peptide backbones, which contain both peptide and ester bonds, could have influenced the transition from simple molecules to biologically relevant polymers through the formation of compartment-like structures. We demonstrate how the nature of early polymerization and self-assembly may have constrained and guided the emergence of peptides as central components of life. Overall, our results propose an assembly-driven model of selection for the modern protein backbone over alternative analogs, offering insights into the transition from prebiotic chemistry to early biochemistry

One of the most fascinating mysteries in the field of origins of life concerns the driving force that led to the selection of today’s 20 universal L-alpha amino acids in biology. An essential aspect of life’s emergence involves the formation of compartments, which offer encapsulation for target molecules and provide protection from hydrolysis in aqueous environments. Thus, polymers capable of assembly may have had a chemical evolutionary advantage over polymers that lacked this ability. We postulated that primordial peptide assembly could be one of the driving forces that led to the chemical selection of alpha amino acids in life today. To test this hypothesis, we generated depsipeptides, oligomers composed of ester bonds and peptide bonds that form readily under mild drying conditions, as model prebiotic peptides. However, it is unknown whether depsipeptides form assemblies in an aqueous environment similarly to peptides and proteins. To test the hypothesis that depsipeptides with alpha backbones will form assemblies more readily than beta backbones, we synthesized depsipeptides using a matrix of eight alpha- and beta-hydroxy acids and six alpha-, beta-, and gamma-amino acids. The reaction products were analyzed by microscopy and a physical stability analyzer to study assembly formation as well as various analytical techniques for chemical analysis. Our results demonstrate assembly formation in depsipeptide systems containing hydrophobic hydroxy acids and indicate that depsipeptide assemblies containing alpha hydroxy acid backbones are significantly more stable than beta analogs. Overall, our results offer an assembly-driven mode of selection for the alpha backbone in present-day biology.