Effect of a cis -4-aminopiperidine-3-carboxylic acid ( cis -APiC) residue on mixed-helical folding of unnatural peptides.

The α/β-peptide 11/9-helix and the β-peptide 12/10-helix belong to "mixed" helices, in which two types of hydrogen bonds with opposite directionality alternate along the helical axis. cis -2-Aminocyclohexanecarboxylic acid ( cis -ACHC) is known to promote these mixed helices and stabilize the helical propensity more than other acyclic β-residues. Application of a mixed-helical backbone still requires sufficient solubility in aqueous solution. In this regard, we chose cis -4-aminopiperidine-3-carboxylic acid ( cis -APiC) as a foldamer building block that can provide both sufficient aqueous solubility and mixed-helical propensity. Conformational analyses of α/β- and β-peptides containing a cis -APiC residue by circular dichroism spectroscopy and single-crystal X-ray crystallography suggest that the incorporation of cis -APiC instead of cis -ACHC can enhance the aqueous solubility of the mixed-helical peptides without any adverse effect on helical folding. In addition, the ratio between right- and left-handed 12/10-helices of β-peptides can be rationalized by relative energies between the local conformations of the cis -APiC residue.