Amino Acid‐Specific, Ribonucleotide‐Promoted Peptide Formation in the Absence of Enzymes

Abstract

Nucleic acids and polypeptides are at the heart of life.I ti si nteresting to ask whether the monomers of these biopolymers possess intrinsic reactivity that favors oligomerization in the absence of enzymes.W eh ave recently observed that covalently linked peptido RNAchains form when mixtures of monomers react in salt-rich condensation buffer.H ere,w e report the results of as creen of the 20 proteinogenic amino acids and four ribonucleotides.N one of the amino acids prevent phosphodiester formation, so all of them are compatible with genetic encoding through RNAc hain growth. A reactivity landscape was found, in whichp eptide formation strongly depends on the structure of the amino acid, but less on the nucleobase.F or example,p roline gives ribonucleotidebound peptides most readily,t yrosine favors pyrophosphate and phosphodiester formation, and histidine gives phosphorimidazolides as dominant products.When proline and aspartic acid were allowed to compete for incorporation, only proline was found at the N-terminus of peptido chains.T he reactivity described here links two fundamental classes of biomolecules through reactions that occur without enzymes,but with amino acid specificity.

Integrated synthesis of nucleotide and nucleosides influenced by amino acids

“…Comparison to an adenosine analytical standard also shows that adenosine, together with a number of isomeric species, is formed in the condensation reaction of P-ribose and adenine (Supplementary Figs. [18][19][20][21][22]. While the canonical forms of AMP and adenosine were confirmed in these experiments, they were not the main products in the dehydration reaction.…”

“…Recently, a mixture of amino acids and ribonucleotides in the presence of an activating agent (i.e. carbodiimide, ethylimidazole, or magnesium chloride) has been shown to lead to the formation of mixed polymers of nucleotides and amino acids 20,21,22 in addition to the formation of oligo-dipeptide backbones using thioester derivatives as mediators 23 .…”

How Small Heterocycles Make a Reaction Network of Amino Acids and Nucleotides Efficient in Water

“…[23] Peptide growth is faster than the background oligomerization of amino acids, [23] and the reaction system is robust, producing biochemically relevant molecules with all 20 proteinogenic amino acids. [24] Among the enzyme-free experimental systems known to us,t he condensation-buffer system produces the largest number of classes of biomolecules.Atypical assay will run continuously for days or weeks without human intervention, making it aprime candidate for studying the principles of an enzyme-free reaction network. Understanding how it functions without falling prey to as ingle dominant reaction or premature hydrolysis requires aq uantitative understanding.…”

Ribonucleotides and RNA Promote Peptide Chain Growth

“…[30] Taken together,t his suggests that RNAh ad the ability to capture and couple amino acids long before either ribozymes or enzymes were formed.…”

“…The rich structure space of peptido RNAs forming with other proteinogenic amino acids and ribonucleotides is reported in the accompanying paper. [30] Table S2 for alist of peak intensities.…”