Genetic Code Evolution Investigated through the Synthesis and Characterisation of Proteins from Reduced-Alphabet Libraries

Matilda S. Newton, Dana J. Morrone, Kun Hwa Lee, Burckhard Seelig

Research output: Contribution to journalArticlepeer-review

10 Scopus citations


The universal genetic code of 20 amino acids is the product of evolution. It is believed that earlier versions of the code had fewer residues. Many theories for the order in which amino acids were integrated into the code have been proposed, considering factors ranging from prebiotic chemistry to codon capture. Several meta-analyses combined these theories to yield a feasible consensus chronology of the genetic code's evolution, but there is a dearth of experimental data to test the hypothesised order. We used combinatorial chemistry to synthesise libraries of random polypeptides that were based on different subsets of the 20 standard amino acids, thus representing different stages of a plausible history of the alphabet. Four libraries were comprised of the five, nine, and 16 most ancient amino acids, and all 20 extant residues for a direct side-by-side comparison. We characterised numerous variants from each library for their solubility and propensity to form secondary, tertiary or quaternary structures. Proteins from the two most ancient libraries were more likely to be soluble than those from the extant library. Several individual protein variants exhibited inducible protein folding and other traits typical of intrinsically disordered proteins. From these libraries, we can infer how primordial protein structure and function might have evolved with the genetic code.

Original languageEnglish (US)
Pages (from-to)846-856
Number of pages11
Issue number6
StatePublished - Mar 15 2019

Bibliographical note

Funding Information:
We thank Dr. Maureen Quin for assistance with the western blots, and Prof. Romas Kazlauskas and Fredarla Miller for their comments on the manuscript. This work was funded in part by grants from the US National Aeronautics and Space Administration (NASA) Agreement (NNX14AK29G), the Simons Foundation (340762), the Minnesota Medical Foundation (4036–9663-10), the University of Minnesota Biocatalysis Initiative, and the Office of the VP of Research at the University of Minnesota (Grant-in-Aid).

Publisher Copyright:
© 2019 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim


  • genetic code
  • origin of proteins
  • primordial peptides
  • protein libraries


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