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Substituting the central proline residue in a collagen mimetic peptide with δ-oxaproline affords a faster-folding analogue with equivalent triple helix stability. 

Collagen, the major structural protein in connective tissue, adopts a right‐handed triple helix composed of peptide chains featuring repeating Gly‐Xaa‐Yaa tripeptide motifs. While the cyclic residues proline (Pro) and hydroxyproline (Hyp) are prevalent in the Xaa and Yaa positions due to their PPII‐favoring conformational properties, diverse acyclic peptoid (N‐alkylated Gly) residues can also stabilize the collagen fold. Here, we investigated the effects of N‐aminoglycine (aGly) derivatives—so‐called “azapeptoid” residues—on the thermal stability of collagen mimetic peptides (CMPs). Substitution of Pro at the central Xaa11 position with aGly resulted in destabilization of the triple helix, yet the introduction of select N′‐alkyl groups (isopropyl, butyl) partially restored thermal stability. Moreover, the N‐amino group of azapeptoid residues enhanced thermal CMP stability relative to an unsubstituted Gly analog. Kinetic studies revealed that the introduction of the hydrazide bonds in aGly and (iPr)aGly CMPs did not significantly impact triple helix refolding rates. Their modular late‐stage derivatization and tunable properties highlight azapeptoid residues as potentially valuable tools for engineering CMPs and probing the structural determinants of collagen folding.