Dataset Information

An Improved Turn Structure for Inducing β-Hairpin Formation in Peptides.

ABSTRACT: Although β-hairpins are widespread in proteins, there is no tool to coax any small peptide to adopt a β-hairpin conformation, regardless of sequence. Here, we report that δ-linked γ(R)-methyl-ornithine (^δ MeOrn) provides an improved β-turn template for inducing a β-hairpin conformation in peptides. We developed a synthesis of protected ^δ MeOrn as a building block suitable for use in Fmoc-based solid-phase peptide synthesis. The synthesis begins with l-leucine and affords gram quantities of the N^α -Boc-N^δ -Fmoc-γ(R)-methyl-ornithine building block. X-ray crystallography confirms that the ^δ MeOrn turn unit adopts a folded structure in a macrocyclic β-hairpin peptide. CD and NMR spectroscopy allow comparison of the ^δ MeOrn turn template to the δ-linked ornithine (^δ Orn) turn template that we previously introduced and to the popular d-Pro-Gly turn template. These studies show that the folding of the ^δ MeOrn turn template is substantially better than that of ^δ Orn and is comparable to d-Pro-Gly.

SUBMITTER: Li X

PROVIDER: S-EPMC8490300 | biostudies-literature | 2021 Oct

REPOSITORIES: biostudies-literature

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Publications

An Improved Turn Structure for Inducing β-Hairpin Formation in Peptides.

Li Xingyue X Sabol Andrew L AL Wierzbicki Michał M Salveson Patrick J PJ Nowick James S JS

Angewandte Chemie (International ed. in English) 20210912 42

Although β-hairpins are widespread in proteins, there is no tool to coax any small peptide to adopt a β-hairpin conformation, regardless of sequence. Here, we report that δ-linked γ(R)-methyl-ornithine (<sup>δ</sup> MeOrn) provides an improved β-turn template for inducing a β-hairpin conformation in peptides. We developed a synthesis of protected <sup>δ</sup> MeOrn as a building block suitable for use in Fmoc-based solid-phase peptide synthesis. The synthesis begins with l-leucine and affords gr ...[more]

PMID: 34258835

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Project description:Protein misfolding disorders are associated with conformational changes in specific proteins, leading to the formation of potentially neurotoxic amyloid fibrils. During pathogenesis of prion disease, the prion protein misfolds into β-sheet rich, protease-resistant isoforms. A key, hydrophobic domain within the prion protein, comprising residues 109-122, recapitulates many properties of the full protein, such as helix-to-sheet structural transition, formation of fibrils and cytotoxicity of the misfolded isoform. Using all-atom, molecular simulations, it is demonstrated that the monomeric 109-122 peptide has a preference for α-helical conformations, but that this peptide can also form β-hairpin structures resulting from turns around specific glycine residues of the peptide. Altering a single amino acid within the 109-122 peptide (A117V, associated with familial prion disease) increases the prevalence of β-hairpin formation and these observations are replicated in a longer peptide, comprising residues 106-126. Multi-molecule simulations of aggregation yield different assemblies of peptide molecules composed of conformationally-distinct monomer units. Small molecular assemblies, consistent with oligomers, comprise peptide monomers in a β-hairpin-like conformation and in many simulations appear to exist only transiently. Conversely, larger assemblies are comprised of extended peptides in predominately antiparallel β-sheets and are stable relative to the length of the simulations. These larger assemblies are consistent with amyloid fibrils, show cross-β structure and can form through elongation of monomer units within pre-existing oligomers. In some simulations, assemblies containing both β-hairpin and linear peptides are evident. Thus, in this work oligomers are on pathway to fibril formation and a preference for β-hairpin structure should enhance oligomer formation whilst inhibiting maturation into fibrils. These simulations provide an important new atomic-level model for the formation of oligomers and fibrils of the prion protein and suggest that stabilization of β-hairpin structure may enhance cellular toxicity by altering the balance between oligomeric and fibrillar protein assemblies.

Dataset Information

An Improved Turn Structure for Inducing β-Hairpin Formation in Peptides.

Publications

An Improved Turn Structure for Inducing β-Hairpin Formation in Peptides.

Similar Datasets

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