Hybrid Sequences that Express both Aromatic Amide and α‐Peptidic Folding Features

Abstract

Foldamers combining aliphatic and aromatic main‐chain units often produce atypical structures that cannot easily be accessed from purely aromatic or aliphatic sequences. We report solid‐state evidence that sequences comprising α‐amino acids and quinoline‐based monomers adopt conformations that combine the folding propensities of both components. Foldamers 2 and 3 having an XQQ repeat motif (X=α‐amino acid, Q=quinoline) were synthesized. Crystals of 2 (X=Phe, Q with an anionic side chain) obtained from water revealed an aromatic helix where amide groups belonging to the α‐amino acids created a hydrogen‐bond array typical of peptidic helices. Crystals of 3 (X=Ser, Q with a lipophilic side chain) obtained from organic solvents revealed a helix‐turn‐helix structure in which α‐amino acid side chains interfere with main‐chain hydrogen bonding. High sequence‐dependency of the conformation is typical of peptides but is shown here to include aromatic folding features.

Conformational interplay in hybrid peptide–helical aromatic foldamer macrocycles

“…No values were found within the left-handed α-helix area, unlike when individual amino acids are inserted within Q n sequences. 10 Thus, the influence of the foldamer helices on the peptides do not extend to the induction of disfavoured conformations.…”

“…Of note, compounds 1-7 may in principle be expressed by the ribosome using a PQPQ-GF initiator, whereas 8-11 are more rigid (8) or longer (9)(10)(11) than what the ribosome has been shown to tolerate until now. 4,5 One may nevertheless consider introducing large and rigid foldamer helices, such as those of 8-11 into hybrid macrocycles through a post-translational modification, i.e.…”

“…Interest for such peptide modifications stems from the high propensity of Q Xxx /P sequences to adopt stable helically folded conformations, particularly in water. 7,8 The folding propensity of Q units is so high that they promote folding in otherwise flexible units, including -amino acids, 9,10 when these flexible units are inserted within Qn oligomers. The folding propensity of P units is weaker.…”

Quaternary Ru(ii) complexes of terpyridines, saccharin and 1,2-azoles: effect of substituents on molecular structure, speciation, photoactivity, and photocytotoxicity

“…† PLAT430 ALERT 2 B (short inter D⋯A contact O3) for complex 5 originated possibly from the hydrogen atom interaction in the three-center CvO (saccharin) and N-H ( pyrazole) or disorder. 72 Photoactivity and singlet oxygen generation…”

Potential Foldamers Based on an ortho-Terphenyl Amino Acid

“…In these systems, stacking of aromatic surfaces, rather than H-bonding, represents the dominant interaction between adjacent helical turns. Huc and co-workers have explored oligomers with alternation of α-amino acid residues and aromatic amino acid residues; the results suggest that interturn stacking and interturn H-bonding may compete with rather than reinforce one another in these systems . β-Peptides and oligoureas assemble into helix bundles. ,,− The multiple noncovalent attractions possible in synthetic foldamer helices (H-bonds, aromatic stacking) open the door to diverse modes of intermolecular interaction. ,− …”