Chain-Length-Dependent Helical Motifs and Self-Association of β-Peptides with Constrained Side Chains

Abstract

Homo-oligomers constructed by using trans-2-aminocyclohexanecarboxylic acid monomers without protecting groups were studied. Both ab initio theory and NMR measurements showed that the tetramer tends to adopt a 10-helix motif, while the pentamer and hexamer form the known 14-helix. It was concluded that the conformationally constrained backbone is flexible enough to afford both 10-helical and 14-helical motifs, this observation in turn providing evidence of the true folding process. Self-association of the helical units was also detected, and the results of variable-temperature diffusion NMR measurements strongly suggested the presence of helical bundles in methanol solution.

β-Peptide foldamer helices with tailored diameters

“…Short β-peptides containing the conformationally constrained alicyclic trans-2-aminocyclohexanecarboxylic acid (trans-ACHC) adopted stable H14 helices in organic solvents and in the solid state. 30,[75][76][77] Trans-4-aminopiperidine-3-carboxylic (trans-APiC) acid residues can also be incorporated into the sequence to form an H14 helix in aqueous solution. 78 Interestingly, Ortuno and co-workers revealed the ability of cis-2-aminocyclobutanecarboxylic acid (cis-ACBC) monomers to promote H14 helical folding when incorporated into β-peptides.…”

“…178 In certain cases, completion of the coupling step is difficult for steric reasons. The application of newer coupling reagents such as uronium salts 30 or microwave-associated coupling conditions 178,179 can ensure the good-quality final products. The current synthetic protocols mostly apply automated Fmoc solid-phase synthesis.…”

“…(Table 1). 113,129 To test this phenomenon on our peptides, DOSY NMR measurements were run and the aggregation numbers were determined in CD3OD from the measured diffusion constants for 3 and 4 in the described manner 118 ( Table 2). In the present work, glucose was utilized as an external reference.…”

“…29,57 The transition from the H10 helix to the H14 helix occurs with the increase of the peptidic chain length for oligomers having trans-ACHC in the sequence. 30 Our aim was to prove the existence of the helix transition and its influencing factors for foldameric oligomers containing the ACHC analogue trans-ABHC and β 3 -hSer residues in various patterns.…”

Tailoring β-peptide foldamers by backbone stereochemistry and side-chain topology

“…An additional consequence of the presence of protecting groups on the termini is their effects on the evolving secondary structure. 26 To avoid the mentioned difficulties and the need for more complex peptides, solid-phase peptide synthesis (SPPS) has been applied, [24][25][26]31,32,53 with both the Boc-based and the Fmocbased strategies. The coupling of conformationally constrained alicyclic β-amino acids is often difficult and becomes very complicated in homo-oligomers after the fourth residue.…”