Structural and Positional Effects of Peptoid Residues on Triple Helix Stability

Area of Science:

• Biochemistry
• Materials Science
• Structural Biology

Background:

• Collagen's triple helix structure is crucial for its stability and function.
• Proline (Pro) and hydroxyproline (Hyp) are key residues for stabilizing the collagen triple helix.
• N-substituted glycines (N-Glys) previously enhanced triple helix stability at the Xaa position.

Purpose of the Study:

• To investigate the impact of N-Glys at the Yaa position on collagen triple helix stability.
• To explore how N-Gly position and side chain structure influence stability.
• To understand the conformational effects of N-Glys in the triple helix.

Main Methods:

• Circular dichroism (CD) spectroscopy.
• X-ray crystallography.
• Computational simulations, including metadynamics.
• Synthesis and characterization of over 22 N-Glys variants.

Main Results:

• N-Glys at the Yaa position support triple helical folding and enhance stability.
• N-Glys are more stabilizing than corresponding amino acids but less than Hyp due to suboptimal angles.
• N-Glys at Yaa positions offer broader conformational flexibility.
• (S)-isomers of chiral N-Glys are essential for triple helix compatibility.
• (S)-N-(1-phenylethyl)-Gly (Nspe) showed significant stabilization via CH···π interactions.

Conclusions:

• N-Glys at the Yaa position represent a viable strategy for stabilizing collagen triple helices.
• Side chain bulkiness of N-Glys primarily affects stability at the Xaa position.
• This work provides insights for designing stable collagen mimetic peptides for biomedical applications.