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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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This content will become publicly available on June 1, 2027
Secondary-Structure-Dependent Cooperation and Interference Between Peptides of Different Chain Lengths in Antifreeze Activity: Insights from Molecular Dynamics Simulations
Ice recrystallization inhibition (IRI) activity of peptides is influenced by both peptide length and secondary structure; however, whether combinations of peptides with different lengths exhibit cooperative or antagonistic effects remains poorly understood. Using molecular dynamics simulations, this study investigated how secondary structure and chain-length heterogeneity jointly affect the IRI activity of peptide-pair mixtures. For systems containing only β-sheet-rich peptides, mixtures of different chain lengths consistently reduced ice content relative to the corresponding single-peptide systems, suggesting cooperative enhancement of IRI activity. In contrast, individual α-helical peptides showed strong inhibition of ice growth, but this effect was diminished after they were mixed into peptide pairs. Structural analyses suggested that the improved performance of β-sheet mixtures was associated less with the simple preservation of native β-sheet structure than with mixing-induced changes in peptide–peptide coupling and surface exposure. By contrast, helix-containing mixtures retained more of their original local structure in some cases, but this structural retention was not accompanied by improved ice-growth suppression after mixing. Together, these findings suggest that peptide length effects on IRI are not universally synergistic but depend strongly on secondary-structure compatibility.
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- Award ID(s):
- 2103558
- PAR ID:
- 10697607
- Publisher / Repository:
- MDPI
- Date Published:
- Journal Name:
- Foods
- Volume:
- 15
- Issue:
- 12
- ISSN:
- 2304-8158
- Page Range / eLocation ID:
- 2228
- Format(s):
- Medium: X
- Sponsoring Org:
- National Science Foundation
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