Abstract
(S)-piperidine-2-carboxylic acid (Pip) is a six-membered ring of proline derivative. Pip has been reported to be associated with hyperpipecolic acidemia－one of the rare disorders, which an increase in pipecolic acid levels in the blood leads to neuropathy and hepatomegaly. In the fist part of this work, we prepared various peptides with Pip incorporated, including polyproline, HP7, and Trp cage. Circular dichroism spectroscopy (CD) was used to characterize their conformation. We found that the incorporation of Pip did not affect polyproline II structure but destabilized polyproline I conformation. When Pip was incorporated into HP7, it seemed to fit well in a β-harpin and did not significantly change the structure. However, the incorporation of Pip into Trp cage dramatically destabilized the α-helical structure, in particular replacing Pro12 to Pip destroyed the structure. We also used a computational approach to study the effect of Pip on polyproline conformation. For each model compound and system, hybrid density functional theory (DFT) calculations, as implemented in Gaussian 09, were carried out to learn the energy difference between different conformations. We used Ac-P2(Pip)P2-NH2 as a model system for the computation. Pip prefers a boat up conformation similar to the Cϒ-exo pucker of Pro, and can also form the conformation of boat down, chair up, and chair down. The calculations indicate that all the conformers of Pip are not appropriate to a PPI helix, which may explain why Pip destabilizes PPI conformation as observed by the experiments. In the second part, we chose Prion octarepeat fragments to study their potential catalytic activity on acyl transfer reaction. The results indicate that it has a high catalytic activity when the Xaa position in Ac-XaaHGGGWGQP-NH2 (GQX) or Ac-GQXaaHGGGWGQ-NH2 (XP) is Asp, and Ac-GQDHGGGWGQ-NH2 (GQD) is more efficient than Ac-GQDHGGGWGQ-NH2 (DP). In GQD, the Asp is at the middle of the peptide, making Asp interact with His more strongly, which might explain why GQD is more effective than DP on catalyzing the reaction.