Kinetics of Prebiotic Depsipeptide Formation from the Ester-Amide Exchange Reaction

In this work, we introduce a kinetic model to study the effectiveness of the ester-mediated amide bond formation under prebiotic conditions. The results of the Miller-Urey experiments and meteorite investigations have provided evidence that amino acids, the building blocks of peptides, existed on the prebiotic earth.¹  However, a prebiotically-plausible process for the polymerization of amino acids is still unclear. In our previous study, we found a simple system composed of hydroxy acids and amino acids is capable of forming peptide bonds via esterification and the ester-amide exchange reaction.²To further understand the kinetic behavior of this complex copolymerization, we first designed a closed reactor to monitor the evaporation of water and lactic acid from the reaction mixture. The growth of initial species from a valine and lactic acid mixture was monitored by HPLC-UV/MS. A mathematical model was developed to simulate the reactions and to evaluate the rate constants at different temperatures. Our results reveal that copolymerization between valine and lactic acid is well-characterized by our model and a small number of physical parameters. We found that these reactions can be described by the empirical Arrhenius equation even when the reactions occurred at a dried state. Further calculations for the activation parameters show that the ester-mediated pathway facilitates amide bond formation primarily by having higher activation entropies. These results provide a theoretical framework that illustrates why the ester-mediated pathway for peptide bond formation would have been more favorable on the early Earth than peptide bond formation without the aid of hydroxy acids.

1. (a) Bernstein, M. P.; Dworkin, J. P.; Sandford, S. A.; Cooper, G. W.; Allamandola, L. J., Racemic amino acids from the ultraviolet photolysis of interstellar ice analogues. Nature 2002, 416 (6879), 401-403; (b) Miller, S. L., A production of amino acids under possible primitive earth conditions. Science 1953, 117(3046), 528-529.

2. Forsythe, J. G.; Yu, S.-S.; Mamajanov, I.; Grover, M. A.; Krishnamurthy, R.; Fernández, F. M.; Hud, N. V., Ester-mediated amide bond formation driven by wet–dry cycles: A possible path to polypeptides on the prebiotic earth. Angew. Chem. Int. Ed. 2015, 54 (34), 9871-9875.