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d -Proline ( D Pro, D P) is widely utilized to form β-hairpin loops in engineered peptides that would otherwise be unstructured, most often as part of a D PG sub-unit that forms a β-turn. To observe whether D PG facilitated this effect in short protonated peptides, conformation specific IR–UV double resonance photofragment spectra of the cold (∼10 K) protonated D P and L P diastereomers of the pentapeptide YAPGA was carried out in the hydride stretch (2800–3700 cm −1 ) and amide I/II (1400–1800 cm −1 ) regions. A model localized Hamiltonian was developed to better describe the 1600–1800 cm −1 region commonly associated with the amide I vibrations. The CO stretch fundamentals experience extensive mixing with the N–H bending fundamentals of the NH 3 + group in these protonated peptides. The model Hamiltonian accounts for experiment in quantitative detail. In the D P diastereomer, all the population is funneled into a single conformer which presented as a type II β-turn with A and D P in the i + 1 and i + 2 positions, respectively. This structure was not the anticipated type II′ β-turn across D PG that we had hypothesized based on solution-phase propensities. Analysis of the conformational energy landscape shows that both steric and charge-induced effects play a role in the preferred formation of the type II β-turn. In contrast, the L P isomer forms three conformations with very different structures, none of which were type II/II′ β-turns, confirming that L PG is not a β-turn former. Finally, single-conformation spectroscopy was also carried out on the extended peptide [YAA D PGAAA + H] + to determine whether moving the protonated N-terminus further from D PG would lead to β-hairpin formation. Despite funneling its entire population into a single peptide backbone structure, the assigned structure is not a β-hairpin, but a concatenated type II/type II′ double β-turn that displaces the peptide backbone laterally by about 7.5 Å, but leaves the backbone oriented in its original direction.
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N -Hydroxy peptides: solid-phase synthesis and β-sheet propensity
Peptide backbone amide substitution can dramatically alter the conformational and physiochemical properties of native sequences. Although uncommon relative to N -alkyl substituents, peptides harboring main-chain N -hydroxy groups exhibit unique conformational preferences and biological activities. Here, we describe a versatile method to prepare N -hydroxy peptide on solid support and evaluate the impact of backbone N -hydroxylation on secondary structure stability. Based on previous work demonstrating the β-sheet-stabilizing effect of α-hydrazino acids, we carried out an analogous study with N -hydroxy-α-amino acids using a model β-hairpin fold. In contrast to N -methyl substituents, backbone N -hydroxy groups are accommodated in the β-strand region of the hairpin without energetic penalty. An enhancement in β-hairpin stability was observed for a di- N -hydroxylated variant. Our results facilitate access to this class of peptide derivatives and inform the use of backbone N -hydroxylation as a tool in the design of constrained peptidomimetics.
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- PAR ID:
- 10175263
- Date Published:
- Journal Name:
- Organic & Biomolecular Chemistry
- Volume:
- 18
- Issue:
- 19
- ISSN:
- 1477-0520
- Page Range / eLocation ID:
- 3690 to 3696
- Format(s):
- Medium: X
- Sponsoring Org:
- National Science Foundation
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- Free Publicly Accessible Full Text
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Accepted Manuscript1.0
- Journal Article:
- https://doi.org/10.1039/D0OB00664E
