pH modulates the TGF-β ligands binding to the receptors: a computational analysis

Area of Science:

• Biochemistry
• Computational Biology
• Molecular Biology

Background:

• Transforming growth factor-beta 1 (TGF-β1) and TGF-β3 share high sequence similarity and form similar ternary complexes in vitro.
• Despite structural similarities, their distinct in vivo roles suggest a lack of functional redundancy, necessitating studies on ligand specificity.
• Understanding the molecular basis of TGF-β1 and TGF-β3 interactions with their receptors is crucial for elucidating their unique biological functions.

Purpose of the Study:

• To comparatively analyze the binary and ternary complexes of TGF-β1 and TGF-β3 using computational methods.
• To identify specific residues involved in ligand-receptor interactions at different interfaces (TGF-β:TβR2 and TGF-β:TβR1).
• To investigate the pH-dependent binding energies and electrostatic interactions governing complex formation.

Main Methods:

• Comparative computational analysis of binary and ternary complexes.
• Identification of anchor and hot residues at ligand-receptor interfaces.
• Delphi analysis to assess pH dependence of binding energy.

Main Results:

• Anchor residues at the TGF-β:TβR2 interface are similar for both ligands, but differ significantly at the TGF-β:TβR1 interface.
• Specific residues (Tyr50, Lys51 for TGF-β3; Lys60, Tyr6 for TGF-β1) and receptor residues (Pro55, Asp57, Ile54/Val61) are identified as key anchors.
• Binding energy of TGF-β3 to TβR2 is pH-dependent, favoring lower pH (4-7), with additional residues contributing at pH 4.
• TβR1 binding shows significant pH dependence in ternary complexes, with electrostatic interactions disfavoring complex formation at pH 7 and favoring it at pH 4 for TGF-β3.

Conclusions:

• TGF-β1 and TGF-β3 exhibit distinct binding specificities at the TGF-β:TβR1 interface, explaining their non-redundant in vivo roles.
• pH significantly influences the binding affinity and stability of TGF-β-receptor complexes, particularly for TβR1 and TGF-β3 interactions.
• The identified specific residues and pH-dependent interactions provide a molecular basis for the differential functions of TGF-β1 and TGF-β3.