University of Sussex
Browse
WRAP-impact-oxetane-incorporation-structure-stability-alpha-helical-peptides-Dixon-2020[68].pdf (1.59 MB)

Impact of oxetane incorporation on the structure and stability of alpha-helical peptides

Download (1.59 MB)
journal contribution
posted on 2023-06-10, 04:59 authored by Eleanor JayawantEleanor Jayawant, Jonathan D Beadle, Ina Wilkening, Piotr Raubo, Michael Shipman, Rebecca Notman, Ann M Dixon
Peptide-based drugs combine advantages of larger biological therapeutics with those of small molecule drugs, but they generally display poor permeability and metabolic stability. Recently, we introduced a new type of peptide bond isostere, in which the backbone carbonyl is replaced with a 3-amino oxetane heterocycle, into short linear peptides with the aim of improving their therapeutic potential. In this study, we have explored the impact of oxetane modification on a-helical peptides to establish whether or not this modification is tolerated in this biologically important structural motif. The oxetane modification was introduced at two positions in a well-characterised helical peptide sequence, and circular dichroism and NMR spectroscopy were used to measure the resulting secondary structure content under different experimental conditions. Our data demonstrated that introduction of an oxetane into the peptide backbone results in a significant loss of helicity, regardless of where in the sequence the modification is placed. The molecular determinants of this destabilisation were then explored using steered molecular dynamics simulations, a computational method analogous to single molecule spectroscopy. Our simulations indicated that oxetane modification introduces a kink in the helical axis, alters the dihedral angles of residues up to three positions away from the modification, and disrupts the (i, i + 4) hydrogen bonding pattern characteristic of a-helices in favour of new, short-range hydrogen bonds. The detailed structural understanding provided in this work can direct future design of chemically modified peptides.

History

Publication status

  • Published

File Version

  • Accepted version

Journal

Physical Chemistry Chemical Physics

ISSN

1463-9076

Publisher

Royal Society of Chemistry (RSC)

Issue

43

Volume

22

Page range

25075-25083

Event location

England

Department affiliated with

  • Clinical and Experimental Medicine Publications

Full text available

  • Yes

Peer reviewed?

  • Yes

Legacy Posted Date

2022-10-04

First Open Access (FOA) Date

2022-10-04

First Compliant Deposit (FCD) Date

2022-10-03

Usage metrics

    University of Sussex (Publications)

    Categories

    No categories selected

    Licence

    Exports

    RefWorks
    BibTeX
    Ref. manager
    Endnote
    DataCite
    NLM
    DC