The impact of 4-thiaproline on polyproline conformation.

Proline is unique among the genetically coded amino acids; because of the presence of a saturated pyrrolidine ring, it favors a cis peptide bond more strongly than other amino acids. The prolyl peptide bond conformational preference can be modulated by alterations to the atoms or substitution groups on the ring. In the study of a simple Ac-Xaa-OMe system, (2R)-4-thiaproline (Thp) was shown to favor an endo ring pucker and a cis prolyl peptide bond. Herein, to investigate the effects of Thp on a more complex system, that is, the polyproline structure, we prepared a series of polyproline peptides with one or multiple proline residues substituted with Thp and used circular dichroism (CD) spectroscopy to characterize their structures. In contrast to the results obtained using the Ac-Xaa-OMe system, here we found that Thp not only destabilizes all-trans polyproline II conformation, but also disfavors all-cis polyproline I structure. On the basis of the hybrid density functional theory analysis, we demonstrate that this phenomenon could be due to the small transition barrier between an exo and an endo pucker for the thiazolidine ring of Thp in a PPI helix and a weak backbone n → π* interaction for Thp in PPII conformation. The combination of experimental and computational data allows us to gain new insights into the impact of 4-thiaproline on polyproline conformation.