Short peptides corresponding to bioactive sequences of proteins rarely show stable structures in water, but when artificially stabilised they can potently modulate protein–protein interactions. 1 7-, 10-, 13-membered hydrogen bonded rings define γ-, β- and α-turns respectively (left) that potentially might be stabilised by cyclisation via side chains (right). Here we investigate tetrapeptides for some new clues to how stereochemical and structural constraints can control folding of the peptide backbone into different turns and helical twists.įig. New insights to peptide folding can also enable design of small molecules capable of mimicking different kinds of turn motifs in proteins. 1), including non-helical α-turns, 4,5 underscoring the importance of gaining a better understanding of how such turn variations dictate local structure and, ultimately, determine function. They include different subtle variations of α-, β- and γ-turns ( Fig. 2 Thousands of protein–protein interfaces are now known to have bioactive ‘hotspots’ localised to just 4–8 amino acid segments (1–2 turns), 3 but 50% of those sequences have nonregular secondary structures. Protein–protein recognition is based on interactions between folded secondary structures like α-helices, β-strands, turns and loops. Introduction Protein structure is directed by inherent preferences of amino acids for different folds, 1 and by packing and solvation effects. These structural models provide insights into stability for different turns and twists corresponding to non-regular folds in protein hotspots. Surprisingly, an unstructured peptide ARLARLARL could be twisted into a helix when either a helical or non-helical alpha turn ( 5, 13, 17, 18, 21–24) with Z = Dap was attached to the N-terminus. A beta or gamma turn was favoured for Z = Dab, Orn or Glu due to a χ1 gauche (+) rotamer, while an alpha turn was favoured for Z = Dap (but not X = Dap) due to a gauche (−) rotamer. Five formed two ( i, i + 3) hydrogen bonds and a beta/gamma ( 6, 7) or beta ( 9, 19, 20) turn eight formed one ( i, i + 4) hydrogen bond and twisted into a non-helical ( 13, 18, 21, 22, 24) or helical ( 5, 17, 23) alpha turn one was less structured ( 15). 2D NMR spectra allowed determination of 3D structures for 14 cyclic tetrapeptides in water. Here we report linking side chains of amino acids X and Z to form 24 cyclic tetrapeptides, cyclo-NH 2, and stabilise 14–18 membered rings that mimic different kinds of non-regular secondary structures found in protein hotspots. Corresponding tetrapeptides have no structure in water. Protein–protein interactions involve hotspots as small as 4 sequential amino acids.
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