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The signature structure of collagen, the triple helix, comprises three collagen strands with GlyXaaYaa repeats intertwining into a right-handed superhelix. Pro and Hyp at the respective Xaa and Yaa positions provides maximum triple helical stability. Previously, we reported that peptoid residues also known as N-substituted Glycines (N-Glys) in the Xaa position generate hyperstable collagen triple helices. Here, we demonstrate that N-Glys at the Yaa position also stabilize the triple helix, with the position (Xaa or Yaa) and side chain structure of N-Gly profoundly affecting the triple helix stability. CD spectroscopy and X-ray crystallography indicated that N-Glys at the Yaa position were more conducive to triple helical folding than amino acids, although they were unable to access the most favorable phi-psi angles for the triple helix represented by Hyp. Metadynamics simulations showed a more diffused conformational space for N-Glys at the Yaa position than at the Xaa position due to minimal steric crowding from neighboring Gly. Only the S-isomers of chiral N-C(alpha) branched N-Glys were compatible with triple helical folding, with differences in backbone conformation and accessible rotamers between Xaa and Yaa positions. At the Yaa position, chiral Nspe can stabilize the triple helix better than any other natural or unnatural residues (except Hyp) via the intrachain CH•••Pi interactions. This work not only deepens our understanding of triple helical folding but also demonstrates a new design strategy for stable collagen mimetic peptides with unprecedented side chain diversity, opening new opportunities for applications in biomedicine and biomaterials.
Bhuket et al. (Mon,) studied this question.