Peptides are sequences of amino acids that can fold into secondary structures such as α-helices and β-sheets. Certain peptides and proteins have the ability to assemble into a complex structure, a characteristic correlated with the formation of plaques in the brains of Alzheimer’s patients. This assembly can be manipulated by the insertion of unnatural amino acids into a polypeptide, which has been shown to disrupt the formation of plaques <i>in vitro</i>. We have examined the synthesis of unnatural amino acids using a metal-ion complex with the intent to incorporate those acids into a peptide to observe changes in folding patterns. In utilizing a metal-ion complex, a variety of unique side-chains can be built onto an amino acid backbone using a dialkylation process. After dialkylation, the complex can then be broken down via hydrolysis to isolate the newly synthesized unnatural amino acids. The metal ion is the centerpiece of the complex and holds together all of the components of the molecule. Removing this ion causes the complex to break apart, revealing the dialkylated amino acid. A large drawback of the standard acid-facilitated hydrolysis is the potential removal of acid-labile protecting groups. As an alternative to this approach, we have previously shown that hydrolysis can be facilitated by ethylenediaminetetraacetic acid (EDTA), a chelating agent that sequesters the nickel ion, increasing the complex’s susceptibility to hydrolysis. However, the increased water content from the EDTA results in a dilute product and low yield in subsequent fluorenylmethyloxycarbonyl (Fmoc) protection reactions. To reduce the water content required for hydrolysis, we are currently studying the ability of different organic-soluble chelating agents to facilitate hydrolysis. Monitoring of this hydrolysis using NMR spectroscopy has shown that citric acid is able to disrupt the complex, resulting in total separation of subcomponents with no residual Ni-PBP-glycine. Plans are in place to conduct more hydrolysis experiments with citric acid in order to obtain more data on the efficiency of citric acid as a chelating agent in these hydrolyses.

Facilitation of hydrolysis of a Ni-Schiff base using varied chelating agents

256th National Meeting (2018)

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