Chain reversals in model peptides: studies of cystine‐containing cyclic peptides II. Effects of valyl residues and possible i‐to‐(i + 3) attractive ionic interactions on cyclization of [Cys1], [Cys6] hexapeptides

Abstract

The synthesis of four N‐acetyl N′‐methylamide cystine‐containing hexapeptides, CVPGVC, CGVVGC, CKPGEC, and CEPGKC, is described. These were used in disulfide‐exchange reactions with the peptide CVPGGC as the formal oxidant. The relative propensities for peptide cyclization were thus deduced, and the tendency toward the formation of chain‐reversal conformations was established quantitatively. An additional peptide, CVVVVC, was prepared but was never obtained as the cyclic monomer, demonstrating that the formation of chain‐reversals in this peptide was of very low probability. Incorporation of pairs of valyl residues decreased the ease of cyclization, but it appeared that conformational flexibility in the cystine‐containing hexapeptides may have compensated for substitutions which would have been expected to hinder the adoption of certain β‐turn conformations. The peptides containing ionic residues were cyclized more readily than expected, and this process was relatively insensitive to salt concentration. This observation is discussed with regard to the stabilization of β‐turns by i‐to‐(i + 3) ionic interactions in peptides and proteins. A method for blocking thiols was introduced as an improvement in the analysis of the equilibrium mixtures.