Design, synthesis and conformations of novel triple helical collagen mimetic structures

Abstract

We have synthesized collagen-like monodisperse structures. A series of single chain Ac-(Gly-Pro-Hyp) n -NH2 wheren=1, 3, 5, 6, 9 and template-assembled KTA-[Gly-(Gly-Pro-Hyp) n -NH2]3 analogs (n=1, 3, 5, 6), where KTA is the Kemp triacid (cis-1,3,5-trimethyl cyclohexane-1,3,5-tricarboxylic acid), were assessed for triple helicity by CD, thermal denaturation and NMR spectroscopy. The KTA-based template induces a significant gain in free energy and reduces the critical chain length for triple helix formation over the acyl terminated single chain structures. Our approach also includes the incorporation of the peptoid residueN-isobutylglycine into the design for novel collagen-like sequences. We have synthesized and characterized acetylated single chain and template-assembled analogs composed of Gly-Pro-Nleu and Gly-Nleu-Pro sequences. The achiral trimeric unit Gly-Nleu-Nleu was included as a guest sequence in a host structure such as Ac-(Gly-Pro-Hyp)3-(Gly-Nleu-Nleu)3-(Gly-Pro-Hyp)3-NH2 which retains triple helicity. A series of guest-host collagen mimetics composed of Gly-Nleu-Pro sequences as the host were synthesized and assessed for triple helicity. Guest sequences include Gly-Nleu-Nleu and Gly-Nx-Pro units, where Nx is the guest peptoid residue with alkyl and aralkyl side chains. We have continued to investigate functionalized template motifs and sequence variations. We are examining the effects of functionalization and sequence variation on triple helical stabilities and molecular properties in order to design novel collagen-based biomaterials.