Mutually stabilizing interactions between proto-peptides and RNA

Moran Frenkel-Pinter,Ramanarayanan Krishnamurthy,Nicholas V Hud,Loren Dean Williams,Luke J Leman,Martin C,Alyssa B Sargon,Anton S Petrov,Jay W Haynes,Ahmad M Mohyeldin

doi:10.1038/s41467-020-16891-5

Moran Frenkel-Pinter, Ramanarayanan Krishnamurthy + Show 8 more

Open Access

https://doi.org/10.1038/s41467-020-16891-5

Copy DOI

Abstract

The close synergy between peptides and nucleic acids in current biology is suggestive of a functional co-evolution between the two polymers. Here we show that cationic proto-peptides (depsipeptides and polyesters), either produced as mixtures from plausibly prebiotic dry-down reactions or synthetically prepared in pure form, can engage in direct interactions with RNA resulting in mutual stabilization. Cationic proto-peptides significantly increase the thermal stability of folded RNA structures. In turn, RNA increases the lifetime of a depsipeptide by >30-fold. Proto-peptides containing the proteinaceous amino acids Lys, Arg, or His adjacent to backbone ester bonds generally promote RNA duplex thermal stability to a greater magnitude than do analogous sequences containing non-proteinaceous residues. Our findings support a model in which tightly-intertwined biological dependencies of RNA and protein reflect a long co-evolutionary history that began with rudimentary, mutually-stabilizing interactions at early stages of polypeptide and nucleic acid co-existence.

Highlights

The close synergy between peptides and nucleic acids in current biology is suggestive of a functional co-evolution between the two polymers
We recently reported the formation of cationic depsipeptides generated from binary mixtures of an α-hydroxy acid (Fig. 1) and a cationic α-amino acid (Fig. 1)[39]
Oligomers were observed to form by all three cationic α-hydroxy (β/γ/ε)-amino acids examined after one week of drying at 85 °C under unbuffered, acidic conditions, as indicated by nuclear magnetic resonance (NMR) and liquid chromatography–mass spectrometry (LC–MS) analysis (Fig. 1c–e and Supplementary Figs. 1–8)

Summary

Introduction

The close synergy between peptides and nucleic acids in current biology is suggestive of a functional co-evolution between the two polymers. We show that cationic protopeptides (depsipeptides and polyesters), either produced as mixtures from plausibly prebiotic dry-down reactions or synthetically prepared in pure form, can engage in direct interactions with RNA resulting in mutual stabilization. We show that cationic polyesters and depsipeptides, generated either as heterogeneous mixtures from dry-down reactions of α-hydroxy acid monomers alone or in combination with α-amino acids, or synthetically prepared in homogeneous pure form, can interact directly with RNA in mutually stabilizing partnerships. These interactions prolong the lifetimes of proto-peptides due to lower rates of backbone ester bond hydrolysis, and render RNA duplexes more stable against thermal denaturation. The results of our study support the idea that the intermolecular interactions between RNA and peptides in extant biology have ancient origins and reflect a long co-evolutionary history

Objectives

Methods

Results

Conclusion