Diffusion model assisted designing self-assembling collagen mimetic peptides as biocompatible materials

Area of Science:

• Biomaterials Science
• Computational Biology
• Peptide Chemistry

Background:

• Collagen's mechanical properties rely on self-assembly, but designing functional collagen mimetic peptides (CMPs) is difficult due to vast sequence possibilities.
• Controlling CMP self-assembly into higher-order structures with specific functions remains a significant challenge in biomaterials development.

Purpose of the Study:

• To develop a computational model for generating self-assembling CMPs with desired structural and functional properties.
• To assess the self-assembly efficiency and functional capabilities of computationally designed CMPs.

Main Methods:

• A diffusion model was trained on human collagen features to generate novel CMP sequences.
• Triple helix formation was assessed for synthetic CMPs.
• Melting temperature (Tm) was used to probe triple-helical and untwisting states, and a predictive model for collagen Tm was developed.
• Chemically synthesized short CMPs and recombinantly expressed long CMPs were evaluated for self-assembly and hydrogel formation.
• The effect of CMPs on osteoblast differentiation was investigated.

Main Results:

• The diffusion model successfully generated CMPs, with 66% exhibiting triple helix self-assembly.
• A predictive model for collagen Tm achieved a state-of-the-art Pearson's correlation of 0.95 by cross-validation and 0.8 for synthetic CMPs.
• Self-assembly of both short and long CMPs was confirmed, with hydrogel formation observed at a low concentration of 0.08% (w/v).
• Five designed CMPs demonstrated the ability to promote osteoblast differentiation.

Conclusions:

• Computer-aided design using diffusion models is a powerful strategy for creating functional, self-assembling CMPs.
• The developed models accurately predict collagen Tm and facilitate the design of peptides with controlled self-assembly.
• These findings open avenues for developing novel biomaterials with tailored mechanical and biological functions.