Tuning the β‐turn segment in designed peptide β‐hairpins: Construction of a stable type I′ β‐turn nucleus and hairpin–helix transition promoting segments

Abstract

Designed octapeptides Boc-Leu-Val-Val-Aib-(D)Xxx-Leu-Val-Val-OMe ((D)Xxx = (D)Ala, 3a;(D)Val, 3c and (D)Pro, 5a) and Boc-Leu-Phe-Val-Aib-(D)Ala-Leu-Phe-Val-OMe (3b) have been investigated to construct models of a stable type I' beta-turn nucleated hairpin and to generate systems for investigating helix-hairpin conformational transitions. Peptide 5a, which contains a central Aib-(D)Pro segment, is shown to adopt a stable type I' beta-turn nucleated hairpin structure, stabilized by four cross-strand hydrogen bonds. The stability of the structure in diverse solvents is established by the observation of all diagnostic NOEs expected in a beta-hairpin conformation. Replacement of (D)Pro5 by (D)Ala/(D)Val (3a-c) results in sequences that form beta-hairpins in hydrogen bonding solvents like CD(3)OH and DMSO-d(6). However, in CDCl(3) evidence for population of helical conformations is obtained. Peptide 6b (Boc-Leu-Phe-Val-Aib-Aib-Leu-Phe-Val-OMe), which contains a centrally positioned Aib-Aib segment, provides a clear example of a system, which exhibits a helical conformation in CDCl(3) and a significant population of both helices and hairpins in CD(3)OH and DMSO-d(6). The coexistence of multiple conformations is established by the simultaneous observation of diagnostic NOEs. Control over stereochemistry of the central beta-turn permits generation of models for robust beta-hairpins and also for the construction of systems that may be used to probe helix-hairpin conformational transitions.

Heterogeneous‐Backbone Foldamer Mimics of a Computationally Designed, Disulfide‐Rich Miniprotein

“…1) in which Pro 12 -Asn 13 was replaced with D-Pro-Gly (peptide 2 ), Aib-Gly (peptide 3 ), or δ-linked Orn (peptide 4 ). In terms of known folding behavior, D-Pro-Gly tends to nucleate type II’ or type I’ turns, [22] Aib-Gly is more diverse in its conformational preferences, [23] and δ 2 -Orn promotes a backbone reversal similar to that formed by D-Pro-Gly. [24] …”

Propensities of peptides containing the Asn‐Gly segment to form β‐turn and β‐hairpin structures

“…19 In addition, Balaram et al have designed b-hairpin peptides in which the central D-Pro-Xaa segment (Xaa 5 Gly, [20][21][22][23] Ala, 22,24 Aib, 22,24 L-Pro, 23,24 and Ac 6 c 24 ; Ac 6 c 5 1-aminocyclohexane-1-carboxylic acid) adopts a type II 0 b-turn in crystals. Balaram et al also designed b-hairpin peptides in which the central Aib-Xaa segment (Xaa 5 Gly, 25 D-Ala, 26,27 and D-Pro, 27,28 ) adopts type I 0 or II 0 b-turns in solution and in crystals. In addition, Masterson et al confirmed the formation of a bhairpin structure by a dodecapeptide in which the central Aib-D-Ala segment adopted a type I 0 b-turn in aqueous solution; this b-hairpin structure was superimposable on the corresponding b-hairpin structure containing the DPro-Gly segment.…”

17 The protein epitope mimetic approach to protein-protein interaction inhibitors

“…ß-Hairpin conformations have been successfully stabilized in linear peptides by exploiting tryptophan zipper motifs (π-π-stacking interactions between cross-ß-strand tryptophans at NHB positions), and related interactions (Eidenschink et al 2009;Russell et al 2002;Wu et al 2010b). The residues in the turn region have a strong infl uence upon ß-hairpin (Raghavender et al 2010;Rai et al 2007), which match the preferred right-handed twist of a hairpin. Other building blocks have been incorporated into turn regions and into the ß-strand regions, including, for example, the 1,2-dihydro-3(6H)-pyridinyl unit that favors extended conformations .…”