Stabilization of the Collagen Triple Helix by O-Methylation of Hydroxyproline Residues

The hydroxylation of proline residues in collagen is the most common posttranslational modification in humans. The hydroxy-lation is stereoselective, affording (2S,4R)-4-hydroxyproline (Hyp) in the Yaa position of the canonical Xaa-Yaa-Gly triad and thereby bestowing marked stabilization upon the collagen triple helix.1 The means by which Hyp stabilizes collagen has engendered dispute. One hypothesis suggests that a network of water molecules links the Hyp hydroxyl groups and main-chain carbonyl groups.2,3 An alternative hypothesis invokes a stereoelectronic effect by which the electronegative oxygen preorganizes the main chain in the proper conformation for triple-helix formation.4 The latter explanation originates from the observation that replacing Hyp with (2S,4R)-4-fluoroproline (Flp) increases triple-helix stability; the fluoro group is strongly electron-withdrawing but cannot participate effectively in a putative hydrogen-bonde