Abstract
How life arose from the prebiotic earth is an enduring question of modern science. Informational self-replicators based on β-sheet forming peptides overcome the limitations of RNA based systems such as prebiotic viability and the strand inhibition problem. This project investigates antiparallel β-sheet forming peptides containing both α- and β3-amino acids (α/β-peptides) for their potential as early earth informational self-replicators. It is hypothesised that the sequence of α and β3 amino acids can function as a proto-genetic code, favouring β-sheet formation between peptides of complementary sequence due to improved alignment of hydrogen bond donors and acceptors. The use of short (α-amino acids) and long (β3-amino acids) informational units suggests a name: Molecular Morse Code (MMC).The impact of MMC on secondary structure was studied using hairpin peptides. A range of hairpin α/β-peptides possessing complementary and non-complementary sequences on their intramolecular β-sheet forming strands were analysed using CD and 2D NMR studies. A clear relationship between sequence complementarity and β-sheet propensity was observed, with structures possessing non-complementary sequence adopting disordered conformations. It was thought that MMC could direct the condensation of peptide fragments such that products of self-complementary α/β-sequence were selected for. A novel ‘hook and fragment’ peptide system derived from earlier hairpins was used to test this notion. The self-replication of α/β-peptides was also studied using linear α/β-peptides to template the condensation of their activated subunits via intermolecular H-bonding. In both these investigations the principal factor governing selectivity was instead found to be reactivity differences of the C-terminal NHS esters used for C-terminal activation, with little influence of MMC towards β-sheet capable self-complementary products. Finally, the potential of MMC to direct the self-sorting of α/β-peptides from complex aqueous mixtures was studied. Three charged 13-residue peptides were found capable of extensive supramolecular assembly into β-sheet bilayer structures and gelation in response to external conditions of pH and temperature. Secondary structure and fibre morphologies were analysed by CD, FTIR and TEM. A study of self-sorting versus co-assembly was carried out on mixed two-component samples which had been triggered to assemble simultaneously by a shared environmental stimulus. Strong evidence was found to support the development of self-sorted double fibre networks from peptide pairings of non-complementary sequence.
This project has demonstrated the capacity of α/β-sequence to direct the secondary structure characteristics, self-assembly and large-scale ordering of short α/β-peptide chains, thus supporting the candidacy of α/β-peptides as informational species with relevance to the emergence of life.
| Date of Award | 5 Dec 2023 |
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| Original language | English |
| Awarding Institution |
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| Supervisor | M C Galan (Supervisor) & Anthony P Davis (Supervisor) |