4‐Chloroprolines: Synthesis, conformational analysis, and effect on the collagen triple helix

Abstract Collagen is an abundant, triple‐helical protein comprising three strands of the repeating sequence: Xaa–Yaa–Gly. (2S)‐Proline and (2S,4R)‐4‐hydroxyproline (Hyp) are common in the primary structure of collagen. Here, we use nonnatural proline derivatives to reveal determinants of collagen stability. Specifically, we report high‐yielding syntheses of (2S,4S)‐4‐chloroproline (clp) and (2S,4R)‐4‐chloroproline (Clp). We find that the molecular structure of Ac‐Clp‐OMe in the solid state is virtually identical to that of Ac‐Hyp‐OMe. In contrast, the conformational properties of Ac‐clp‐OMe are similar to those of Ac‐Pro‐OMe. Ac‐Clp‐OMe has a stronger preference for a trans amide bond than does Ac‐Pro‐OMe, whereas Ac‐clp‐OMe has a weaker preference. (Pro–Clp–Gly) 10 forms triple helices that are significantly more stable than those of (Pro–Pro–Gly) 10 . Triple helices of (clp–Pro–Gly) 10 have stability similar to those of (Pro–Pro–Gly) 10 . Unlike (Pro–Clp–Gly) 10 and (clp–Pro–Gly) 10 , (clp–Clp–Gly) 10 does not form a stable triple helix, presumably due to a deleterious steric interaction between proximal chlorines on different strands. These data, which are consistent with previous work on 4‐fluoroprolines and 4‐methylprolines, support the importance of stereoelectronic and steric effects in the stability of the collagen triple helix and provide another means to modulate that stability. © 2007 Wiley Periodicals, Inc. Biopolymers 89: 443–454, 2008. This article was originally published online as an accepted preprint. The “Published Online” date corresponds to the preprint version. You can request a copy of the preprint by emailing the Biopolymers editorial office at biopolymers@wiley.com