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Issue 29, 2020
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Unusually high α-proton acidity of prolyl residues in cyclic peptides

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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.

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

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Supplementary files

Article information


Submitted
03 May 2020
Accepted
02 Jul 2020
First published
02 Jul 2020

This article is Open Access
All publication charges for this article have been paid for by the Royal Society of Chemistry

Chem. Sci., 2020,11, 7722-7729
Article type
Edge Article

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

O. R. Maguire, B. Taylor, E. M. Higgins, M. Rees, S. L. Cobb, N. S. Simpkins, C. J. Hayes and A. C. O'Donoghue, Chem. Sci., 2020, 11, 7722
DOI: 10.1039/D0SC02508A

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