γ‐Azaproline Confers pH Responsiveness and Functionalizability on Collagen Triple Helices

Proline derivatives bearing substituents at Cγ are valuable tools for biological and materials investigations. However, the stereochemistry at Cγ can produce undesired steric or stereoelectronic interactions. Here, we introduce γ‐azaproline (γ‐azPro), which lacks a stereogenic center at Cγ, as a pH‐responsive and functionalizable proline analogue that can adapt to its environment. Conformational analyses by NMR spectroscopy and DFT calculations revealed that the imidazolidine ring of γ‐azPro is flexible. Incorporation of γ‐azPro into collagen model peptides (CMPs) produced pH‐responsive triples helices and triple helices that can be easily functionalized. A chemical chameleon: γ‐Azaproline was introduced as a pH‐responsive and functionalizable amino acid with a conformation that can adapt to the environment. Incorporation into collagen triple helices showed its value as a tool to functionalize peptides and proteins and render them pH‐responsive.