The PH dependent mechanisms of peptide bond cleavage

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Sun, Yi
Grover, Martha A.
Liotta, Charles L.
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The origin of life under prebiotic conditions has been an unsolved mystery for decades. Amino acids were available under prebiotic conditions, and different approaches of amino acids condensation into proto-polypeptides have been well designed, giving rise to a prebiotic soup with various peptide sequences. The emergence of functional biopolymers involves not only polymerization into longer species, but also the selective process with some species being protected and enriched over time. In this project, we treated peptide bond cleavage as the driving force for the selection process, by reshuffling peptide sequences and thus increasing the rate of search through sequence space. As a result, understanding the reaction mechanisms and quantifying the degradation kinetics of various peptide species is necessary to design a prebiotically plausible system that can demonstrate chemical evolution. In this project, we conducted fundamental research studies to understand the impact of pH on the peptide degradation reaction kinetics and mechanisms. The degradation rate of the amide bonds in oligopeptides in aqueous solution is pH-dependent and is suggested to involve two distinct mechanism: direct hydrolysis (herein termed “scission”) and backbiting. While amide degradation was studied previously using various peptides, no systematic study has been reported addressing the separate rates of amide bond degradation over a wide pH range via these two mechanisms. In this study, the degradation kinetics of several short oligopeptides, specifically the glycine dimer, trimer, and cyclic dimer, as well as the alanine trimer, were measured at 95oC over a range of pH conditions using 1H NMR. The rate constants were obtained by solving the differential equations based on mechanistic models and elucidate the favored reaction pathway under acidic, neutral, and basic pH conditions. The degradation rate of the glycine trimer is much faster than the dimer under the acidic and neutral pH conditions. The glycine dimer degradation rate is highest under acidic and basic conditions, while the glycine trimer degradation rate is highest under neutral pH conditions. The results suggest that while the glycine dimer undergoes ring opening purely through a scission reaction mechanism, the glycine trimer is degraded through both backbiting and scission reaction mechanisms. At an acidic pH of 3, both mechanisms are active, while at neutral pH backbiting is dominant. In contrast, at a basic pH of 10, scission dominates.
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