title: 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. (
authors.affiliation: Department of Chemistry, University of Wisconsin-Madison, Madison, WI 53706-1322, USA.
authors.forename: Matthew D
authors.initials: MD
authors.lastname: Shoulders
authors.forename: Ilia A
authors.initials: IA
authors.lastname: Guzei
authors.forename: Ronald T
authors.initials: RT
authors.lastname: Raines
mesh_terms: D019943:Amino Acid Substitution; D002942:Circular Dichroism; D003094:Collagen / Q000737:chemistry* / Q000187:drug effects*; D018360:Crystallography, X-Ray; D015394:Molecular Structure; D009842:Oligopeptides / Q000138:chemical synthesis / Q000737:chemistry; D011392:Proline / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000737:chemistry*; D017433:Protein Structure, Secondary; D017434:Protein Structure, Tertiary
chemical_list: C530187:4-chloroproline; D009842:Oligopeptides; D003094:Collagen; D011392:Proline