A hyperstable collagen mimic

Background: Collagen is the most abundant protein in animals. Each polypept ide chain of collagen is composed of repeats of the sequence: Gly-X-Y, wher e X and Y are often L-proline (Pro) and 4(R)-hydroxy-L-proline (Hyp) residu es, respectively. These chains are wound into tight triple helices of great stability, The hydroxyl group of Hyp residues contributes much to this con formational stability. The existing paradigm is that this stability arises from interstrand hydrogen bonds mediated by bridging water molecules, This model was tested using chemical synthesis to replace Hyp residues with 4(R) -fluoro-L-proline (Flp) residues. The fluorine atom in Flp residues does no t form hydrogen bonds but does elicit strong inductive effects, Results: Replacing the Hyp residues in collagen with Flp residues greatly i ncreases triple-helical stability. The free energy contributed by the fluor ine atom in Flp residues is twice that of the hydroxyl group in Hyp residue s. The stability of the Flp-containing triple helix far exceeds that of any untemplated collagen mimic of similar size. Conclusions: Bridging water molecules contribute little to collagen stabili ty. Rather, collagen stability relies on previously unappreciated inductive effects. Collagen mimics containing fluorine or other appropriate electron -withdrawing substituents could be the basis of new biomaterials for restor ative therapies.