The shielding effect of metal complexes on the binding affinities of ligands to metalloproteins

Metal ions are important regulatory cofactors in a wide variety of proteins. Conventional wisdom suggests that stronger metal-ligand interactions have a larger effect on the ligand binding affinity. However, some experimental data do not support this conventional wisdom. In this study, we used a theoretical derivation approach to explore the effect of metal-ligand interactions on ligand binding affinities. Both theoretical derivation and experimental data indicate that metal-ligand interactions weaken the original interactions of the metal ions, which reduce the contributions of the metal-ligand interactions to the ligand binding affinities. The shielding effect is so large that some strong metal-ligand interactions contribute little to the ligand binding affinities. The binding free energies contributed by metal-ligand interactions have a limited relationship with the strengths of the interactions. Considering that the shielding effect of metal complexes is essential for accurately modelling metal-ligand interactions, our findings challenge the conventional wisdom and represent a significant advance for the design of drugs targeted for metalloproteins and for exploring the enormous catalytic power of metalloproteins.