The β-turn scaffold of tripeptide containing an azaphenylalanine residue

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• 关键词：Azapeptide ; β ; -Turn ; NMR ; Molecular dynamics
• 刊名：Biophysical Chemistry
• 出版年：2007
• 期刊代码：11_03014622
• 类别：ch
• 出版时间：January 2007
• 卷：125
• 期：1
• 页码：117-126
• 文件大小：820 K

摘要

The conformational preferences of azaphenylalanine-containing peptide were investigated using a model compound, Ac-azaPhe-NHMe with ab initio method at the HF/3-21G and HF/6-31G levels, and the seven minimum energy conformations with trans orientation of acetyl group and the 4 minimum energy conformations with cis orientation of acetyl group were found at the HF/6-31G level if their mirror images were not considered. An average backbone dihedral angle of the 11 minimum energy conformations is = ± 91° ± 24°, ψ  = ± 18° ± 10° (or ± 169° ± 8°), corresponding to the i + 2 position of β-turn (δ_R) or polyproline II (β_P) structure, respectively. The χ₁ angle in the aromatic side chain of azaPhe residue adopts preferentially between ± 60° and ± 130°, which reflect a steric hindrance between the N-terminal carbonyl group or the C-terminal amide group and the aromatic side chain with respect to the configuration of the acetyl group. These conformational preferences of Ac-azaPhe-NHMe predicted theoretically were compared with those of For-Phe-NHMe to characterize the structural role of azaPhe residue.

Four tripeptides containing azaPhe residue, Boc-Xaa-azaPhe-Ala-OMe [Xaa = Gly(1), Ala(2), Phe(3), Asn(4)] were designed and synthesized to verify whether the backbone torsion angles of azaPhe reside are still the same as compared with theoretical conformations and how the preceding amino acids of azaPhe residue perturb the β-turn skeleton in solution. The solution conformations of these tripeptide models containing azaPhe residue were determined in CDCl₃ and DMSO solvents using NMR and molecular modeling techniques. The characteristic NOE patterns, the temperature coefficients of amide protons and small solvent accessibility for the azapeptides 1–4 reveal to adopt the β-turn structure. The structures of azapeptides containing azaPhe residue from a restrained molecular dynamics simulation indicated that average dihedral angles [(₁, ψ₁), (₂, ψ₂)] of Xaa-azaPhe fragment in azapeptide, Boc-Xaa-azaPhe-Ala-OMe were [(− 68°, 135°), (116°, − 1°)], and this implies that the intercalation of an azaPhe residue in tripeptide induces the βII-turn conformation, and the volume change of a preceding amino acid of azaPhe residue in tripeptides would not perturb seriously the backbone dihedral angle of β-turn conformation. We believe such information could be critical in designing useful molecules containing azaPhe residue for drug discovery and peptide engineering.