Ester-mediated amide bond formation: A possible path to proto-peptides on the early earth

The formation of polypeptides on the early Earth has been a long-standing problem in the field of prebiotic chemistry. Although it is generally accepted that amino acids were present on the prebiotic Earth, the plausible mechanism to form long chain polypeptides is still unclear. Because of the high activation energies and the formation of side-products, direct peptide bond formation is slow unless high temperature or activating agents are used. This thesis describes a simple system composed of hydroxy acids and amino acids that is capable of forming peptide bonds under mild conditions. Hydroxy acids form metastable oligoesters in the oscillating (hot dry/cool wet) environment and transform into mixed copolymers via the ester-amide exchange reaction. This pathway enables the amide bond formation in lower temperature and leads to a library of oligomers with random sequences when multiple amino acids mix together. To further understand the kinetic behavior of this copolymerization, the growth of initial species from a valine/ lactic acid mixture in a closed system reactor was tracked. A mathematical model was developed to simulate the reactions and evaluate the rate constants at different temperatures. These reactions can be described by the empirical Arrhenius equation even when the reaction occurred in the solid (dry) state. Further calculations for activation parameters showed that the ester-mediated pathway facilitates amide bond formation by lowering activation entropies. In the final part of this thesis, fresh monomers were added to the oligomer mixture periodically in the wet-dry cycling. The feeding composition was found to affect the growth rate of oligomer chain length. The combination of the esterification and ester-amide exchange is similar to the behavior of the living polymerization. Adding more hydroxy acids creates more active chains, but does not necessary elongate the oligomer chains. The average chain length grows more rapidly when the number of active chains is limited. The results from this thesis demonstrate a simple system exhibiting key features for the emergence of peptides at mild conditions and provide a theoretical framework that illustrates why the ester-mediated pathway would have been more favorable on the early Earth, compared to peptide bond formation without the aid of hydroxy acids.Ph.D