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

Maguire, Oliver R.; Taylor, Bethany; Higgins, Eleanor M.; Rees, Matthew; Cobb, Steven L.; Simpkins, Nigel S.; Hayes, Christopher J.; O'Donoghue, AnnMarie C.

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Oliver R. Maguire

Bethany Taylor

Eleanor M. Higgins

Matthew Rees

Nigel S. Simpkins

Christopher J. Hayes


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.


Maguire, O. R., Taylor, B., Higgins, E. M., Rees, M., Cobb, S. L., Simpkins, N. S., …O'Donoghue, A. C. (2020). Unusually high α-proton acidity of prolyl residues in cyclic peptides. Chemical Science, 11(29), 7722-7729.

Journal Article Type Article
Acceptance Date Jul 2, 2020
Online Publication Date Jul 2, 2020
Publication Date 2020-08
Deposit Date Aug 19, 2020
Publicly Available Date Aug 19, 2020
Journal Chemical Science
Print ISSN 2041-6520
Electronic ISSN 2041-6539
Publisher Royal Society of Chemistry
Peer Reviewed Peer Reviewed
Volume 11
Issue 29
Pages 7722-7729


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