Widespread coacervation on early Earth: phase separation in primitive peptide/oligonucleotide mixtures

All modern life forms are cell-based, with membranes composed of diverse and complex phospholipids that likely arose only after the advent of enzymatic synthesis. Recent studies suggest that nucleotides and amino acids could have formed and polymerized non-enzymatically under prebiotic conditions, giving rise to short oligonucleotides and peptides capable of facilitating non-enzymatic RNA replication and peptide synthesis. Before the emergence of lipid membranes, coacervation may have provided a mechanism for the spontaneous formation of protocells.

To test this hypothesis, we investigated phase separation in mixtures of peptides as short as trimers and oligonucleotides as simple as eight nucleobases. Our results demonstrate the early and likely inevitable emergence of primitive coacervates through liquid-liquid phase separation of prebiotic, heterogeneous mixtures of short, non-coded oligonucleotides and peptides. Peptide/nucleic acid coacervates form under a broader range of conditions and exhibit greater stability than peptide/peptide analogues. Notably, salt stability shows a linear dependence on polymer length, allowing us to predict the minimal structural requirements for coacervation in different environments.

Using atomistic simulations and FRAP measurements, we identify key differences between DNA- and RNA-based coacervates for the first time. The more extended and less structured conformation of RNA compared to DNA allows for more contact points with peptides. The additional interactions enhance the salt and thermal stability of peptide/RNA coacervates, while also reducing their fluidity relative to their DNA counterparts.

As an advantage of enhanced diffusion in peptide/DNA coacervates, we demonstrate efficient non-enzymatic primer extension in coacervates for the first time. Our findings support the early emergence of coacervates in origins-of-life scenarios and encourage a re-evaluation of prebiotic chemistry within biphasic systems.