Decoding the dynamics of BCL9 triazole stapled peptide.

Area of Science:

• Computational chemistry and structural biology
• Molecular dynamics simulations
• Peptide design and drug discovery

Background:

• The Wnt signaling pathway is crucial in cellular processes, and its dysregulation is linked to tumor growth.
• BCL9 protein acts as a co-activator in this pathway, interacting with β-catenin.
• Inhibiting the β-catenin/BCL9 interaction is a therapeutic challenge, with peptides mimicking BCL9's helical domain being a promising strategy.

Purpose of the Study:

• To investigate the conformational behavior of single and double triazole stapled BCL9 peptides using molecular dynamics simulations.
• To explore how triazole staples influence the secondary structure and conformational space of BCL9 peptides.
• To validate the findings using Replica Exchange with Solute Tempering (REST2) simulations.

Main Methods:

• Molecular dynamics (MD) simulations were performed on experimentally synthesized single and double triazole stapled BCL9 peptides.
• Replica Exchange with Solute Tempering (REST2) simulations were used to assess high-temperature responses.
• Principal Component Analysis (PCA) and t-distributed Stochastic Neighbor Embedding (t-SNE) were employed for data analysis.

Main Results:

• Triazole stapling significantly reduced the conformational space of the BCL9 peptide.
• The helical character of the stapled peptide increased with greater separation between triazole cross-linkers.
• REST2 simulations, analyzed via PCA and t-SNE, showed reduced distinct cluster formation upon triazole staple addition.

Conclusions:

• Triazole stapling is an effective strategy for stabilizing the helical structure of BCL9 peptides.
• The study provides insights into the underlying interactions governing the secondary structure of stapled peptides.
• These findings support the further development of triazole-stapled BCL9 peptides as potential inhibitors of the β-catenin/BCL9 interaction for cancer therapy.