De novo design, synthesis and solution conformational study of two didehydroundecapeptides: effect of nature and number of amino acids interspersed between Phe residues

Abstract

De novo design of peptides and proteins has recently surfaced as an approach for investigating protein structure and function. This approach vitally tests our knowledge of protein folding and function, while also laying the groundwork for the fabrication of proteins with properties not precedented in nature. The success relies heavily on the ability to design relatively short peptides that can espouse stable secondary structures. To this end, substitution with α,β-didehydroamino acids, especially α,β-didehydrophenylalanine (Δ(z)Phe), comes in use for spawning well-defined structural motifs. Introduction of ΔPhe induces β-bends in small and 3(10)-helices in longer peptide sequences. The present work aims to investigate the effect of nature and the number of amino acids interspersed between two ΔPhe residues in two model undecapeptides, Ac-Gly-Ala-ΔPhe-Ile-Val-ΔPhe-Ile-Val-ΔPhe-Ala-Gly-NH(2) (I) and Boc-Val-ΔPhe-Phe-Ala-Phe-ΔPhe-Phe-Leu-Ala-ΔPhe-Gly-OMe (II). Peptide I was synthesized using solid-phase chemistry and characterized using circular dichroism spectroscopy. Peptide II was synthesized using solution-phase chemistry and characterized using circular dichroism and nuclear magnetic resonance spectroscopy. Peptide I was designed to examine the effect of incorporating β-strand-favoring residues like valine and isoleucine as spacers between two ΔPhe residues on the final conformation of the resulting peptide. Circular dichroism studies on this peptide have shown the existence of a 3(10)-helical conformation. Peptide II possesses three amino acids as spacers between ΔPhe residues and has been reported to adopt a mixed 3(10)/α-helical conformation using circular dichroism and nuclear magnetic resonance spectroscopy studies.

Revisiting 310-helices: biological relevance, mimetics and applications

“…In contrast, they are achiral molecules unable to discriminate themselves alone the screw sense in helical structures, so they are usually combined with chiral proteinogenic amino acids. In particular, the alkene residues from α,β-dehydrophenylalanine (ΔPhe) and α,β-dehydroleucine (ΔLeu) were found to promote the formation of β-turns and 3 10 -helices (Figure 10A) [172][173][174][175][176][177][178]. Recently, a systematic study by Joaquin et al [179] was published aiming to compare the effect of small (α,β-dehydroalanine; ΔAla), medium-sized (α,β-dehydro-2-aminobutyric acid; ΔAbu), and bulky dehydroamino acids (α,β-dehydrovaline; ΔVal) on pentapeptide models containing a Pro residue at the i + 2 position.…”

Conformation of dehydropentapeptides containing four achiral amino acid residues – controlling the role of L-valine

“…The introduction of (Z)-dehydrophenylalanine stabilizes a β-turn conformation even in the case of short peptides [8–10]. This influence is stronger for peptides with a longer main chain, for which a 3 10 -helical conformation could be observed [8,11–13]. Peptides containing a dehydroalanine residue usually have an inverse γ-turn conformation [7,14–15].…”