Biosignatures & Paleobiology

Xeno Amino Acid Alphabets Form Peptides With Familiar Secondary Structure

By Keith Cowing

Press Release

February 10, 2026

Filed under amino acid, biochemistry, biorxiv.org, canonical amino acid, codon, genomics, nucleic acid, Peptides, Xeno Amino Acids

Xeno Amino Acid Alphabets Form Peptides With Familiar Secondary Structure — The experimental pipeline, from design to characterization, of peptides comprising the Xeno 1 and Xeno 2 amino acid alphabets. Design begins with a library of commercially available amino acids. The physicochemical properties (Van der Waals volume and hydrophobicity at pH 7) are then estimated for a xeno alphabet heuristic search. The potential energy surfaces for each amino acid which returns in the search is calculated and two xeno amino acid alphabets, Xeno 1 and Xeno 2, are selected based on post-search metrics (e.g. PCA and EMD). The similarity of these alphabets to the E10 is further assessed via calculation of HOMO-LUMO gaps and LogS: their ability to form secondary structures is measured in vitro with ECD, IR, and NMR spectroscopy for random combinatorial 25-mer libraries and for designed sequences. — biorxiv.org

The central dogma of molecular biology describes how genetic information stored in nucleic acids guides the formation of structured proteins from a single molecular alphabet of twenty amino acids (C20)1,2.

The extent to which C20 is uniquely capable of forming structural polymers remains a fundamental open question. Here we demonstrate that peptides built from other, “xeno” amino acid alphabets can adopt protein-like secondary structural motifs. Having designed two different xeno alphabets, with them we constructed both combinatorial random sequence libraries and specific, designed 25-mer sequences.

We report sequence-dependent structural motifs that result according to circular dichroism, infrared spectroscopy and nuclear magnetic resonance interpreted by molecular dynamics simulations, supported by extensive quantum mechanical calculations. This evidence, including a solution-phase NMR-resolved helical motif, demonstrates that the potential for amino acids to form structure bearing sequences is not unique to life’s alphabet, and thereby reveals a previously unexplored sequence-structure space.

Results inform the search for extraterrestrial life, lay foundations for incorporating novel synthetic functional groups and heteroatoms into structure-bearing alphabets, and provide the first truly independent data with which to test and improve all that has been learned about protein folding from the study of life’s 20 side chains.

Xeno amino acid alphabets form peptides with familiar secondary structure, biorxiv.org (open access)

Astrobiology, Astrochemistry,

Keith Cowing

Explorers Club Fellow, ex-NASA Space Station Payload manager/space biologist, Away Teams, Journalist, Lapsed climber, Synaesthete, Na’Vi-Jedi-Freman-Buddhist-mix, ASL, Devon Island and Everest Base Camp veteran, (he/him) 🖖🏻

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