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

In spite of showing high sequence similarity and forming structurally similar ternary complex in vitro, the in vivo role of TGF-ß1 and TGF-ß3 ligands suggests against their functional redundancy and necessitates the importance for the study of the specificity of these ligands. A comparative computational analysis of binary and ternary complexes of these two ligands shows that anchor residues of ligand and receptor at TGF-ß:TßR2 interface are similar in both complexes. However, the potential anchor residues of TGF-ß at TGF-ß:TßR1 interface are different, Tyr50 and Lys51 in TGF-ß3 complex and Lys60 and Tyr6 in TGF-ß1 complex. Pro55 and Asp57 of TßRI may act as anchor residues in complexes of both ligands along with Ile54 for TGF-ß3 complex and Val61 for TGF-ß1 complex. Arg58 of TßR1 acts as a potential hot residue for TGF-ß3 ternary complex but not for TGF-ß1 ternary complex formation whereas Pro55 and Phe60 may act as hot residues for both complexes. The Delphi analysis of the pH dependence of the binding energy indicates that pH has a remarkable effect on the binding energy of TßR2 to the open form of TGF-ß3. Lowering of pH from 7 to 4 favors binding of the open form of TGF-ß3 to TßR2. Now, apart from the residues at pH 7, residues Arg25, Lys31 and Arg94 of TGF-ß3 and Asp118 and Glu119 of TßR2 also contribute significantly to the binding energy. Contrary to the binding energy of TßR2 to TGF-ß3/TGF-ß1, TßR1 shows appreciable pH dependence for its binding in ternary complex of TGF-ß3/TGF-ß1. In TGF-ß3 ternary complex, the TßR1 electrostatic interaction energy disfavors complex formation at pH 7 while it is favored at pH 4.