Synthesis of superbly hyperstable collagen triple helices via integration of steric and stereoelectronic effects

ORGN 654

Matthew D. Shoulders, shoulders@wisc.edu, Department of Chemistry, University of Wisconsin - Madison, 1101 University Ave., Madison, WI 53706 and Ronald T. Raines, Departments of Chemistry and Biochemistry, University of Wisconsin—Madison, 433 Babcock Drive, Madison, WI 53706.
In previous work, we demonstrated that 4-fluoroproline residues can contribute greatly to the conformational stability of the collagen triple helix, and that this stability arises from stereoelectronic effects that fix the pucker of the pyrrolidine ring and thereby preorganize the backbone properly for triple-helix formation. However, the stability conferred by 4-fluoroprolines to collagen faces an upper limit due to a deleterious steric interaction when they are incorporated in both the Xaa and Yaa positions of a collagen triple helix. We have discovered a reciprocal approach, namely that the steric effect of a 4-methyl group confers stability similar to that from a 4-fluoro group in the opposite configuration. By judicious integration of the steric and stereoelectronic effects we have now prepared collagen triple helices with greater thermal stability than any other collagen peptides of similar size.