Collis, Arran Michael; (2025) Investigations in the prebiotic chemistry of thioethers. Doctoral thesis (Ph.D), UCL (University College London).

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Abstract

The hypothesis central to the experimental work in this thesis is that the components of the extant coding apparatus coemerged. A scenario is thus envisaged in which “life” is in its early stages, and primitive peptide-encoding systems based on nucleic acids are beginning to form. The general chemical synthesis of peptides of length greater than two requires an N-terminal capping group (e.g. an acetyl group), otherwise peptide synthesis terminates with formation of diketopiperazines (DKPs). N-terminal capping is a central feature of prebiotic peptide syntheses, such as the one reported by Canavelli et al., and would also have been necessary for template-directed peptide synthesis in a primitive coding system. However, the efficiency of iterative (monomer by monomer) peptide synthesis decays exponentially with peptide length. The efficient synthesis of long peptides would therefore have required convergent synthesis strategies. For this to be possible, it would have been necessary for the N-cap to be removed from coded peptides, freeing their N-termini for ligation to growing peptide chains. Furthermore, one would expect primitive coding systems to have been error prone, and peptides synthesised inaccurately by such systems would have constituted waste products. N- cap removal induces the degradation of peptides to DKPs, which can then be released to the environment, providing a plausible mechanism for degradation and removal of waste peptides. However, acetyl groups are stable under the conditions compatible with Watson- Crick base pairing (pH 5 – 9), so they cannot easily be removed by direct hydrolysis. This thesis details the discovery of a prebiotically plausible method of N-cap removal which draws direct inspiration from extant biology. A mysterious feature of the extant coding apparatus is the universal start codon, which always encodes methionine. The methionyl side chain contains a thioether, which is generally chemically inert. However, electrophiles such as cyanogen bromide are known to react with methionyl thioethers, inducing fragmentation in the C-terminal direction. It was found that the methionyl thioether undergoes a similar reaction with the prebiotically plausible feedstock, cyanoacetylene, efficiently inducing fragmentation of N-capped methionine peptides at pH 5 - 7. The side chains of histidine and cysteine were derivatised in this reaction, and the latter can be suppressed through oxidation. This fragmentation chemistry was shown to be compatible with prebiotic peptide ligation chemistry, allowing fragmentation products to be reintroduced into a ligation cycle or degraded. This work suggests that the early coding apparatus evolved around methionine’s unique fragmentation chemistry, providing a chemical rationale for its assignment to the universal start codon. Further work is necessary to demonstrate the compatibility of this chemistry with nucleic acid templated peptide synthesis. Branching off from this work, activation of thioethers with cyanoacetylene was found to induce methyl transfer chemistry, proceeding most efficiently when the thioether is in excess. This reaction provides a prebiotically plausible means of generating trimethylsulphonium salts. Further work is required to make this chemistry more efficient, and demonstrate methyl transfer to other substrates. Efficient synthesis of long peptides requires convergent strategies. Along these lines, an expressed peptide ligation strategies proceeding from cysteine fragmentation was investigated. The necessary cysteine cyanation chemistry was found to be capricious, but excellent yields were obtained by adding a catalytic thioether. Further work is required to optimise the cyclisation and acyl transfer steps. Native chemical ligation strategies were also explored by testing the ligation of a thiol containing peptide with N-acetylglycine nitrile, with the conclusion that S – N acyl transfer does not occur appreciably for ring sizes larger than five.

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