AlphaFold2-Guided Cyclic Peptide Stabilizer Design to Target Protein-Protein Interactions.

Area of Science:

• Computational biology
• Drug discovery
• Molecular biophysics

Background:

• Protein-protein interactions (PPIs) are crucial for biological processes.
• Stabilizing PPIs is a growing area of pharmaceutical interest.
• Traditional small molecules have limitations in targeting PPIs due to insufficient interaction surfaces.

Purpose of the Study:

• To develop a computational protocol for designing cyclic peptides that stabilize protein-protein interactions.
• To optimize dual binding of cyclic peptides to two protein partners simultaneously.
• To create bifunctional molecules for targeted protein degradation.

Main Methods:

• A modified AlphaFold2-based peptide design approach was employed.
• The protocol combines confidence scoring with force field-based scoring using Molecular Dynamics simulations.
• The method was validated on known protein-protein complexes with cyclic peptide binders.

Main Results:

• Designed cyclic peptides demonstrated comparable or superior calculated interaction scores to known binders.
• The designed peptides exhibited well-balanced interactions with both protein partners.
• The protocol successfully designed cyclic peptides for targeted protein degradation.

Conclusions:

• The developed computational protocol enables rapid and systematic design of cyclic peptides for PPI modulation.
• Cyclic peptides are a promising class of molecules for stabilizing PPIs and developing bifunctional therapeutics.
• This approach has broad applicability in designing cyclic peptides for biomedical applications.