Thoma, Benjamin; (2024) Chemical studies into the aetiology of proteinogenic amino acids. Doctoral thesis (Ph.D), UCL (University College London).

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Abstract

The universal nature of the genetic code suggests its deep-seated origin. How an early translational apparatus came to be, and why life encodes the particular set of proteinogenic amino acids remains a mystery. This aetiological question is, in chemical terms, a question of selectivity. Prior to the emergence of evolved catalysts, simple, but selective, nonenzymatic chemistry would have dictated which (pre)biological structures could have formed en route to extant life. The reactivity of hydrogen cyanide and nitriles are chemically predisposed to furnish key biological molecules. This chemistry has previously been investigated as a means to synthesise the building blocks of RNA and DNA. However, the nature of informational polymers is deeply entwined with that of proteins and peptides. Here, we present nitrile-based aqueous chemistry that is both capable of synthesising peptides and explaining why life encodes the specific amino acids that it does. In Section 1, we overview the current state of the field, describe relevant aspects of biochemistry and explain why efficient aqueous chemistry is most relevant to origins of life research. In Section 2.1, the reactivity of C-terminal lysine homologues is investigated through the lens of N-to-C terminal peptide ligation and thioester synthesis. We elucidate chemical reasons for why lysine contains the optimal sidechain amine for nonenzymatic peptide ligation, but find that its homologue, 2,3-diaminopropionic acid, is also capable of forming peptides. Moving on to the properties of lysine and 2,3-diaminopropionic acid monomers in Section 2.2, we investigate their prebiotic synthesis and acylation to form αpeptides in the presence of azaphilic metals. Departing from aqueous chemistry in Section 2.3, we then contrast the dry-state acylation of lysine monomers with their aqueous acylation, and demonstrate the shortcomings of removing (pre)biological molecules from their native aqueous environment. Next, a highyielding synthesis of 2,3-diaminopropionic acid sidechains is achieved through sidechain modification of a C-terminal dehydroalanine in Section 2.4. Preliminary studies into a photochemical synthesis of lysine and histidine through sidechain modification of a similar dehydroalanine-derived motif are also presented. Finally, in Section 2.5 and 2.6, we use catalytic thiols to enact an α-selective synthesis of lysine peptides and a δ-selective synthesis of arginine peptides from ornithine monomers. Together, these results highlight the viability of applying chemical rationale to the origin of life. Careful consideration of reactivity and reaction pathways through directed chemical experimentation can demonstrate how biomolecules formed, and why they look like they do.

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