Origin of the stability conferred upon collagen by fluorination

According to a prevailing theory, (2S,4R)-4-hydroxyproline (Hyp) residues stabilize the collagen triple helix via a stereoelectronic effect that preorganizes appropriate backbone torsion angles for triple-helix formation. This theory is consistent with the marked stability that results from replacing the hydroxyl group with the more electron-withdrawing fluoro group, as in (2S,4R)-4-fluoroproline (Flp). Nonetheless, the hyperstability of triple helices containing Flp has been attributed by others to the hydrophobic effect rather than a stereoelectronic effect. We tested this hypothesis by replacing Hyp with 4,4-difluoroproline (Dfp) in collagen-related peptides. Dfp retains the hydrophobicity of Flp, but lacks the ability of Flp to preorganize backbone torsion angles. Unlike Flp, Dfp does not endow triple helices with elevated stability, indicating that the hyperstability conferred by Flp is not due to the hydrophobic effect.

(2S,4R)-4-Fluoroproline residues stabilize the collagen triple helix by the gauche effect—a stereoelectronic effect that enforces a Cg-exo ring pucker and thus properly preorganizes the torsion angles in the backbone.Figure optionsDownload as PowerPoint slide