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Durham University

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Publication details for Prof. AnnMarie C. O'Donoghue

Maguire, Oliver R., Taylor, Bethany, Higgins, Eleanor M., Rees, Matthew, Cobb, Steven L., Simpkins, Nigel S., Hayes, Christopher J. & O'Donoghue, AnnMarie C. (2020). Unusually high α-proton acidity of prolyl residues in cyclic peptides. Chemical Science 11(29): 7722-7729.

Author(s) from Durham

Abstract

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 by 3–89 fold relative to other amino acid residues (prolyl > glycyl ≫ alanyl > tyrosyl). Experimental and computational evidence for the stereoelectronic origins of this enhanced prolyl reactivity is presented. TKPs were 106-fold more reactive than their DKP analogues towards deprotonation, which we attribute to the advanced development of aromaticity in the earlier transition state for proton transfer in these cases. A Brønsted linear free energy analysis of the reaction data was conducted to provide estimates of α-proton pKas.