Cis-trans proline isomerization effects on collagen triple-helix stability are limited.

We investigated the effect of restricting cis-trans proline isomerization on collagen triple-helix stability. The Pro residues at the Xaa and Yaa positions of an (Xaa-Yaa-Gly) triplet were replaced by a Pro-trans-Pro alkene isostere in the host-guest peptide, H-(Pro-Pro-Gly)(10)-OH. The resulting alkene isostere peptide had a T(m) value 53.6 degrees C lower than that of the control peptide. The Pro-trans-Pro alkene isostere peptide had a T(m) value 3.9 degrees C higher than that of the previously reported Pro-trans-Gly alkene isostere peptide that did not involve cis-trans Pro isomerization (Jenkins, C. L.; Vasbinder, M. M.; Miller, S. J.; Raines, R. T. Org. Lett. 2005, 7, 2619-22). Thus, single cis-trans proline amide isomerization alone has limited contribution to the overall stability of the collagen triple helix. Since collagen has a high content of imino acid residues, the cumulative effects of cis-trans isomerization may be quite significant. The peptide containing the Pro-trans-Pro isostere was significantly less stable than the previously reported Gly-trans-Pro alkene isostere peptide that retained the backbone interchain hydrogen bond (Dai, N.; Wang, X. J.; Etzkorn, F. A. J. Am. Chem. Soc. 2008, 130, 5396-5397), which confirms that direct interchain backbone hydrogen bonding is a major force for stabilizing the collagen triple helix.