Inviting Trifluoromethylated Pseudoprolines into Collagen Model Peptides

Numerous Collagen Model Peptides (CMPs) have been engineered using proline derivatives substituted at their C(3) and/or C(4) position in order to stabilize or to functionalize collagen triple helix mimics. However, no example has been reported so far with C(5) substitutions. Here, we introduce a fluorinated CMP incorporating trifluoromethyl groups at the C(5) position of pseudoproline residues. In tripeptide models, our NMR and Molecular Dynamics (MD) studies have shown that, when properly arranged, these residues meet the structural requirements for triple helix assembly. A host-guest CMP could be synthesized and its NMR analysis in solution confirmed the presence of structured homotrimers that we interpret as triple helices. MD calculations showed that the triple helix model remained stable throughout the simulation, with all six trifluoromethyl groups pointing outwards from the triple helix. Pseudoprolines substituted at the C(5) positions appeared as valuable tools for the design of new fluorinated collagen mimicking peptides.