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
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 DixonPeptide-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 PhysicsISSN
1463-9076Publisher
Royal Society of Chemistry (RSC)External DOI
Issue
43Volume
22Page range
25075-25083Event location
EnglandDepartment affiliated with
- Clinical and Experimental Medicine Publications
Full text available
- Yes
Peer reviewed?
- Yes
Legacy Posted Date
2022-10-04First Open Access (FOA) Date
2022-10-04First Compliant Deposit (FCD) Date
2022-10-03Usage metrics
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