Structural Basis for TGF-β Mimetic Peptide-Induced Signaling Activation Through Molecular Dynamics Simulations.

Area of Science:

• Biochemistry
• Molecular Biology
• Computational Biology

Background:

• Transforming growth factor-β (TGF-β) mimetic peptides present therapeutic advantages over native cytokines.
• Two previously identified peptides, TB1 and TB2, bind the type II TGF-β receptor (TβRII) but induce different cellular effects.

Purpose of the Study:

• To elucidate the mechanistic basis for the distinct cellular responses of TGF-β mimetic peptides TB1 and TB2.
• To investigate the structural dynamics and receptor interactions governing peptide activity.

Main Methods:

• Integrated molecular dynamics (MD) simulations utilizing AlphaFold3-predicted structures.
• Analysis of receptor-peptide complex stability, binding affinity, and interaction interfaces.
• Experimental validation using Western blot to assess Smad3 pathway activation.

Main Results:

• TB2 forms a stable, dynamic complex with TβRII, facilitating type I receptor (TβRI) engagement via a key hydrogen bond.
• The TB2-TβRII-TβRI assembly shows enhanced binding affinity and stability compared to TB1-TβRII.
• TB2, but not TB1, activates the TGF-β/Smad pathway, increasing Smad3 expression and phosphorylation.

Conclusions:

• The study reveals the dynamic structural determinants underlying the differential activity of TGF-β mimetic peptides.
• TB2's ability to stabilize a functional ternary complex explains its distinct biological outcome.
• TB2 is identified as a promising lead for developing novel tissue-regenerative therapies.