Proto‐proteins in Protocells

Abstract

Phase separation, and coacervates in particular, may have played a key role in the transition from an abiotic to a biotic world, in providing early membrane‐less compartments and promoting metabolism. Herein, we highlight another potential role of coacervates in providing the milieu in which short abiotically formed peptides evolved gradually into structured, functional proteins. Coacervates, amyloids, and other rudimentary forms of self‐assembly enable short peptides to form supramolecular structures, thus providing the level of structural pre‐organization and complexity needed for biochemical function. Coacervates, however, are unique in also enabling co‐assembly of peptides and nucleic acids, and in promoting the acquisition of helical structures. These two properties, combined with their potential to promote the synthesis of biopolymers, make coacervates a feasible springboard for the emergence of the early nucleic acids binding proteins. Herein, we outline this putative evolutionary scenario and the evidence supporting it, also regarding the emergence of cationic amino acids that are critical to coacervate formation.

Peptide-RNA Coacervates as a Cradle for the Evolution of Folded Domains

“…A central challenge in the field of protein evolution is to understand how the complex structures of contemporary biology could have emerged “from so simple a beginning.” It has been previously argued that independently folding nucleic acid-binding domains, such as the (HhH) 2 -Fold, may be evolutionarily continuous with simple, flexible peptides that form coacervates with RNA (Figure ). , The key intermediate in this hypothetical trajectory is a coacervate formed by a partially folded peptide that interacts with RNA. This intermediate bridges coacervates formed by flexible, compositional peptides interacting with RNA and folded dsDNA-binding domains.…”

“…Little is known, however, about peptide-RNA coacervates as a site for the evolution of protein structure and function, and it is uncertain to what extent phase-separating polypeptides were a resource for the evolution of more complex protein structures. 6 Even the effect of the coacervate context on protein structure and oligomerization is unclear: On the one hand, coacervates are characterized by a network of weak, transient, multivalent interactions between polypeptide and RNA molecules 1 , 7 that, collectively, may favor extended peptide conformations—especially for peptides with marginal folding energies. After all, unstructured peptides can readily form coacervates with nucleic acids 8 (though they do not necessarily do so).…”

“…Liquid–liquid phase separation (LLPS) is an important biological process − with notable relevance to the primordial world, , particularly as a way for simple peptides and nucleic acids to achieve compartmentalization and concentration. Little is known, however, about peptide-RNA coacervates as a site for the evolution of protein structure and function, and it is uncertain to what extent phase-separating polypeptides were a resource for the evolution of more complex protein structures . Even the effect of the coacervate context on protein structure and oligomerization is unclear: On the one hand, coacervates are characterized by a network of weak, transient, multivalent interactions between polypeptide and RNA molecules , that, collectively, may favor extended peptide conformationsespecially for peptides with marginal folding energies.…”

Peptide-RNA Coacervates as a Cradle for the Evolution of Folded Domains

“…A central challenge in the field of protein evolution is to understand how the complex structures of contemporary biology could have emerged 'from so simple a beginning.' We have previously argued that independently folding nucleic acid-binding domains, such as the (HhH)2-Fold, may be evolutionarily continuous with simple, flexible peptides that form coacervates with RNA (Figure 8) 6,17 . The key intermediate in this hypothetical trajectory is a coacervate formed by a partially folded peptide that interacts with RNA.…”

“…Liquid-liquid phase separation is an important biological process [1][2][3] with notable relevance to the primordial world 4,5 , particularly as a way for simple peptides and nucleic acids to achieve compartmentalization and concentration. Little is known, however, about peptide-RNA coacervates as a site for the evolution of protein structure and function, and it is uncertain to what extent phase separating polypeptides were a resource for the evolution of more complex protein structures 6 . Even the effect of the coacervate context on protein structure and oligomerization is unclear: On the one hand, coacervates are characterized by a network of weak, transient, multivalent interactions between polypeptide and RNA molecules 1,7 that, collectively, may favor extended peptide conformationsespecially for peptides with marginal folding energies.…”