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.

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.

Citation

Maguire, O. R., Taylor, B., Higgins, E. M., Rees, M., Cobb, S. L., Simpkins, N. S., Hayes, C. J., & O'Donoghue, A. C. (2020). Unusually high α-proton acidity of prolyl residues in cyclic peptides. Chemical Science, 11(29), 7722-7729. https://doi.org/10.1039/d0sc02508a

• Journal Article Type: Article
• Acceptance Date: Jul 2, 2020
• Online Publication Date: Jul 2, 2020
• Publication Date: Aug 7, 2020
• Deposit Date: Jul 20, 2020
• Publicly Available Date: Jul 20, 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
• DOI: https://doi.org/10.1039/d0sc02508a
• Keywords: General Chemistry
• Public URL: https://nottingham-repository.worktribe.com/output/4773115
• Publisher URL: https://pubs.rsc.org/en/content/articlelanding/2020/SC/D0SC02508A#!divAbstract
• Additional Information: : This document is Similarity Check deposited; : Supplementary Information; : Oliver R. Maguire (ORCID); : Steven L. Cobb (ORCID); : Nigel S. Simpkins (ORCID); : Christopher J. Hayes (ORCID); : AnnMarie C. O'Donoghue (ORCID); : Single-blind; : Received 3 May 2020; Accepted 2 July 2020; Accepted Manuscript published 2 July 2020; Advance Article published 13 July 2020