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The acidity of the α-proton in peptides has an essential role in numerous biochemical reactions and underpins their stereochemical integrity, which is critical to their biological function. We report a detailed kinetic and computational study of the acidity of the α-proton in two cyclic peptide systems diketopiperazine (DKP) and triketopiperazine (TKP). The kinetic acidity (protofugality) of the α-protons were determined though hydrogen deuterium exchange studies in aqueous solutions. The acidities of the α-proton in prolyl residues were increased b