Comparison of helix-stabilizing effects of α,α-dialkyl glycines with linear and cycloalkyl side chains

Abstract

The ability of alpha, alpha-di-n-alkyl glycines with linear and cyclic alkyl side chains to stabilize helical conformations has been compared using a model heptapeptide sequence. The conformations of five synthetic heptapeptides (Boc-Val-Ala-Leu-Xxx-Val-Ala-Leu-OMe, Xxx = Ac8c, Ac7c, Aib, Dpg, and Deg, where Ac8c = 1-aminocyclooctane-1-carboxylic acid, Ac7c = 1-aminocycloheptane-1-carboxylic acid, Aib = alpha-aminoisobutyric acid, Dpg = alpha,alpha-di-n-propyl glycine, Deg = alpha,alpha-di-n-ethyl glycine) have been investigated. In crystals, helical conformations have been demonstrated by x-ray crystallography for the peptides, R-Val-Ala-Leu-Dpg-Val-Ala-Leu-OMe, (R = Boc and acetyl). Solution conformations of the five peptides have been studied by 1H-nmr. In the apolar solvent CDCl3, all five peptides favor helical conformations in which the NH groups of residues 3-7 are shielded from the solvent. Successive NiH<-->Ni + 1H nuclear Overhauser effects over the length of the sequence support a major population of continuous helical conformations. Solvent titration experiments in mixtures of CDCl3/DMSO provide evidence for solvent-dependent conformational transitions that are more pronounced for the Deg and Dpg peptides. Solvent-dependent chemical shift variations and temperature coefficients in DMSO suggest that the conformational distributions in the Deg/Dpg peptides are distinctly different from the Aib/Acnc peptides in a strongly solvating medium. Nuclear Overhauser effects provide additional evidence for the population of extended backbone conformations in the Dpg peptide, while a significant residual population of helical conformations is still detectable in the isomeric Ac7c peptide in DMSO.

Amino-Terminal Parathyroid Hormone Fragment Analogs Containing α,α-di-alkyl Amino Acids at Positions 1 and 3

“…The findings thus lend support to the hypothesis that the amino‐terminal domain of PTH is α‐helical when bound to the receptor (10,14) . Several derivatives of Aib have been described that are also di‐substituted at C α but with alkyl side chains that are longer than the di‐methyl groups of Aib and that may be in linear (e.g., diethyl‐glycine) or cyclic (e.g., 1‐amino‐cyclopentane‐1‐carboxylic acid) configuration (19–23) . These di‐alkyl amino acids are predicted to impose local restrictions on peptide backbone bond rotations that are similar to those imposed by Aib, while displaying side chains that are topologically distinct from those of Aib (Fig.…”

“…As with Aib, the cycloalkane and Deg amino acids used in our PTH analogs have the capacity to stabilize helical backbone structure (19–23) . It is reasonable, therefore, to postulate that our modified PTH analogs adopt at least some α‐helical structure.…”

Cyclooxygenase‐2 expression in medullary thyroid carcinoma

“…In this section, we show how the concept of kernels allows for accurate calculation of peptide energy. All of their crystal structures are known 9–19 and have been used in the energy calculations presented here. Table II illustrates a variety of natural and synthetic peptides which vary in size, shape, and function.…”

The side‐chain hydroxy groups of a cyclic α,α‐disubstituted α‐amino acid promote oligopeptide 310‐helix packing in the crystalline state

“…Nonproteinogenic amino acids such as α,α‐disubstituted α‐amino acids (dAA), cyclic β‐amino acids, and cross‐linked side‐chains are often utilized as tools for peptide helix stabilization. Among dAA, α‐aminoisobutyric acid (Aib), α‐methylated dAA, and achiral cyclic dAA have been shown to be useful for stabilizing peptide helices. However, most of the dAA developed to date were produced with the aim of restricting the dihedral angles of the peptide backbone in order to stabilize helical structures.…”