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.