Mimicry of βII′‐turns of proteins in cyclic pentapeptides with one and without d‐amino acids

Abstract

The solution structure of eight cyclic pentapeptides has been determined by two-dimensional 1H-NMR spectroscopy combined with spectra simulations and restrained molecular dynamic simulations. Six of the cyclic pentapeptides were derived from the C-terminal cholecystokinin fragment CCK-4 enlarged with Asp1 resulting in the sequence (Asp-Trp-Met-Asp-Phe), one L-amino acid after the other was substituted by its D-analog. In addition, two peptides, including an all-L-amino-acid-containing cyclic pentapeptide, cyclo(Asp-Phe-Lys-Ala-Thr) and cyclo(Asp-Phe-Lys-Ala-D-Thr) were investigated. All D-amino-acid-containing peptides show beta II'-turn conformations with the D-amino acid in the i + 1 position, excepting the D-aspartic-acid-containing peptides. These two peptides are characterized by the lack of beta-turns at pH values less than 4, suggesting that D-aspartic acid in the full-protonized state avoids the formation of beta-turns in these compounds. At pH values greater than 5, a conformational change into the beta II'-turn conformation was also observed for these peptides. Conformations without beta-turns are expected for cyclic all-L pentapeptides, but both cyclo(Asp-Phe-Lys-Ala-Thr) and the D-Thr analog cyclo(Asp-Phe-Lys-Ala-D-Thr) exhibit beta II'-turn conformations around Thr-Asp and D-Thr-Asp. Thus cyclic all-L pentapeptides and those with one D-amino acid are able to form similar structures preferably with a beta II'-turn. The beta-turn formation in cyclic pentapeptides containing a D-aspartic acid is dependent on the ionization state. The relevance of the work to the design of beta'-turn mimetics is discussed.

Immunogenicity of Peptide-vaccine Candidates Predicted by Molecular Dynamics Simulations

“…D-Cysteine and D-lysine-SAMA were chosen for position i þ 1 of peptides C and D, because D-amino acids are known to stabilize a reverse turn by favoring positive f angles. 28 A glycine residue was chosen for position i þ 2, as this amino acid can adopt the correct f,c-angles (908, 08 for type I 0 and 2 808, 08 for type II 0 ). In order to have a higher overlap in sequences of peptide and protein, the amino acid residues at positions i and i þ 3 were chosen to be the same as in the cognate protein, i.e.…”

New conformationally homogeneous β‐turn antagonists of the human B2 kinin receptor

“…On the basis of the Thurieau results [19], indicating that stabilizing the conformation via cyclization is beneficial for the antagonistic activity and with the aim of designing new low molecular weight molecules, we focused our efforts on studying cyclic derivatives that would preserve the type-II% b-turn conformation around the D-Tic-Oic sequence independently of the residues in position i and i+ 3 of the turn. This would allow the introduction of different amino acids (alkyl, aromatic, polar and charged) ( Figure 1) without changing the overall ring structure [20,21], thereby permitting a systematic analysis of their effect upon binding to the human B 2 receptor. The availability of a conformationally homogeneous series, in which all the peptides share a common structure, is the information required for the design of a first generation peptidomimetic, in which a suitable non-peptidic scaffold will replace the backbone.…”

Investigation of the interaction between the atypical agonist c[YpwFG] and MOR

“…The cyclopeptide compound 3 , c [YpwFG], showed good MOR affinity (Table 1), and agonist behavior (forskolin‐stimulated cAMP production inhibition test) [20]. Cyclic peptides have been widely used as conformationally restricted frameworks [21], useful for arranging the pharmacophores in different reciprocal orientations, and in particular, cyclic pentapeptides containing one or two d ‐amino acids have been successfully utilized as β‐turn or γ‐turn models [22–27]. The hypothesis that EM‐1 derivatives could adopt at the receptor a folded structure stabilized by some kind of γ‐turn or β‐turn has been stressed in recent papers [8,28,29].…”