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Impact of oxetane incorporation on the structure and stability of alpha-helical peptides
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Jayawant, Eleanor, Beadle, Jonathan D., Wilkening, Ina, Raubo, Piotr, Shipman, Michael, Notman, Rebecca and Dixon, Ann M. (2020) Impact of oxetane incorporation on the structure and stability of alpha-helical peptides. Physical Chemistry Chemical Physics, 22 (43). pp. 25075-25083. doi:10.1039/D0CP03818K
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WRAP-impact-oxetane-incorporation-structure-stability-alpha-helical-peptides-Dixon-2020.pdf - Accepted Version - Requires a PDF viewer. Download (2196Kb) | Preview |
Official URL: http://dx.doi.org/10.1039/D0CP03818K
Abstract
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 α-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 α-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.
| Item Type: | Journal Article | ||||||||||||
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| Subjects: | Q Science > QD Chemistry Q Science > QP Physiology |
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| Divisions: | Faculty of Science > Engineering Faculty of Science > Physics |
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| Library of Congress Subject Headings (LCSH): | Peptides -- Synthesis, Circular dichroism, Molecular dynamics, Proteins -- Chemical modification | ||||||||||||
| Journal or Publication Title: | Physical Chemistry Chemical Physics | ||||||||||||
| Publisher: | Royal Society of Chemistry | ||||||||||||
| ISSN: | 1463-9076 | ||||||||||||
| Official Date: | 21 October 2020 | ||||||||||||
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| Volume: | 22 | ||||||||||||
| Number: | 43 | ||||||||||||
| Page Range: | pp. 25075-25083 | ||||||||||||
| DOI: | 10.1039/D0CP03818K | ||||||||||||
| Status: | Peer Reviewed | ||||||||||||
| Publication Status: | Published | ||||||||||||
| Access rights to Published version: | Restricted or Subscription Access | ||||||||||||
| RIOXX Funder/Project Grant: |
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