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Unusually high α-proton acidity of prolyl residues in cyclic peptides.

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


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.

Item Type:Article
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Publisher statement:This article is licensed under a Creative Commons Attribution 3.0 Unported Licence.
Date accepted:02 July 2020
Date deposited:19 August 2020
Date of first online publication:02 July 2020
Date first made open access:19 August 2020

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