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α, β Hybrid Peptides: A Polypeptide Helix with a Central Segment Containing Two Consecutive β-Amino Acid Residues

Conformational studies on the synthetic 11-aa peptide t-butoxy-carbonyl (Boc)-Val-Ala-Phe-α-aminoisobutyric acid ( Aib)-(R)-β3-homovaline (β Val)-(S)-β3-homophenylalanine (βPhe)-Aib-Val-Ala-Phe-Aib-methyl ester (OMe) (peptide 1; βVal and βPhe are β amino acids generated by homologation of the corres...

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Published in:Proceedings of the National Academy of Sciences - PNAS 2004-11, Vol.101 (47), p.16478-16482
Main Authors: Roy, Rituparna S., Karle, Isabella L., Raghothama, S., Balaram, P.
Format: Article
Language:English
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Summary:Conformational studies on the synthetic 11-aa peptide t-butoxy-carbonyl (Boc)-Val-Ala-Phe-α-aminoisobutyric acid ( Aib)-(R)-β3-homovaline (β Val)-(S)-β3-homophenylalanine (βPhe)-Aib-Val-Ala-Phe-Aib-methyl ester (OMe) (peptide 1; βVal and βPhe are β amino acids generated by homologation of the corresponding L-residues) establish that insertion of two consecutive β residues into a polypeptide helix can be accomplished without significant structural distortion. Crystal-structure analysis reveals a continuous helical conformation encompassing the segment of residues 2-10 of peptide 1. At the site of insertion of the ββ segment, helical hydrogen-bonded rings are expanded. A C15hydrogen bond for the αββ segment and two C14hydrogen bonds for the ααβ or βαα segments have been characterized. The following conformational angles were determined from the crystal structure for the β residues: βVal-5 (φ = -126°, θ = 76°, and ψ = -124) and βPhe-6 (φ = -88°, θ = 80°, and ψ = -118). The N terminus of the peptide is partially unfolded in crystals. The 500-MHz1H- NMR studies establish a continuous helix over the entire length of the peptide in CDCl3solution, as evidenced by diagnostic nuclear Overhauser effects. The presence of seven intramolecular hydrogen bonds is also established by using solvent dependence of NH chemical shifts.
ISSN:0027-8424
1091-6490
DOI:10.1073/pnas.0407557101