Designed β‐hairpin peptides with defined tight turn stereochemistry

Abstract

The conformational analysis of two synthetic octapeptides, Boc-Leu-Val-Val-D-Pro-L-Ala-Leu-Val-Val-OMe (1) and Boc-Leu-Val-Val-D-Pro-D-Ala-Leu-Val-Val-OMe (2) has been carried out in order to investigate the effect of beta-turn stereochemistry on designed beta-hairpin structures. Five hundred megahertz (1)H NMR studies establish that both peptides 1 and 2 adopt predominantly beta-hairpin conformations in methanol solution. Specific nuclear Overhauser effects provide evidence for a type II' beta-turn conformation for the D-Pro-L-Ala segment in 1, while the NMR data suggest that the type I' D-Pro-D-Ala beta-turn conformation predominates in peptide 2. Evidence for a minor conformation in peptide 2, in slow exchange on the NMR time scale, is also presented. Interstrand registry is demonstrated in both peptides 1 and 2. The crystal structure of 1 reveals two independent molecules in the crystallographic asymmetric unit, both of which adopt beta-hairpin conformations nucleated by D-Pro-L-Ala type II' beta-turns and are stabilized by three cross-strand hydrogen bonds. CD spectra for peptides 1 and 2 show marked differences, presumably as a consequence of the superposition of spectral bands arising from both beta-turn and beta-strand conformations.

Reinvestigation of the proposed folding and self‐association of the Neuropeptide Head Activator

“…These unusual types of β‐turn are commonly observed at the loops of 2:2 β‐hairpins in proteins (Wilmot and Thornton 1988). The d ‐Pro‐Gly segment has been shown to promote β‐hairpin formation in several short designed peptides (Haque et al 1996; Haque and Gellman 1997; Stanger and Gellman 1998; Das et al 2001). Furthermore, the incorporation of d ‐Pro into reverse turns has also been employed in several instances to stabilize antiparallel β‐sheet interactions between short strand segments derived from natural proteins outside the context of the natural tertiary structure (Struthers et al 1996; Haque and Gellman 1997; Espinosa and Gellman 2000; Kaul et al 2001).…”

A Crystalline β-Hairpin Peptide Nucleated by a Type I′ Aib-D-Ala β-Turn: Evidence for Cross-Strand Aromatic Interactions

“…Of the four anticipated cross‐strand hydrogen bonds in an idealized β‐hairpin, the terminal interaction Leu(1) NH⋅⋅⋅OC Val(8) is disrupted by a large reorientation about the C α CO bond of Val(8) ( ψ =−57.3°). Such fraying at hairpin termini is not uncommon 8c. Residues Leu(1), Phe(2), Val(3), and Leu(6) adopt ϕ and ψ values characteristic of β‐sheets, while some distortion is observed at Phe(7), which takes up a “polyproline‐like” conformation ( ϕ =−69.9°, ψ =+140.5°).…”

Interplay between hydrophobic cluster and loop propensity in β‐hairpin formation: A mechanistic study

“…1), expected to adopt a more highly defined β‐hairpin conformation than 1 . The arrangement of the Trp, Tyr, Phe, and Val residues in 2 allows side chain juxtapositions (characterizing the natural peptide 1 ) if the peptide folds to a β‐hairpin conformation with a tight two‐residue loop; the D‐Pro‐Gly segment strongly promotes this type of β‐hairpin (Espinosa and Gellman 2000; Das et al 2001). Espinosa and Gellman (2000) showed by NMR‐NOE experiments, chemical shift analysis, and circular dycroism that peptide 2 tends to adopt pairing of antiparallel β‐strands similar to that of peptide 1 at two different temperatures of 275K and 315K.…”