Metal Binding in Proteins: The Effect of the Dielectric Medium

In proteins as well as host molecules, metal ions generally bind to a shell of polar hydrophilic residues surrounded by a shell of nonpolar hydrophobic groups. The hydrophilic protein residues tend to bind directly to the metal ( inner-sphere mode), instead of indirectly via a metal-bound water molecule ( outer-sphere mode). However, it is not fully understood why metal ions tend to bind in an inner-sphere fashion and at centers of high hydrophobic contrast. Ab initio and continuum dielectric calculations have been employed to compute the free energy (Δ G ex ) of the exchange reaction between a metal-bound water molecule and ligands of biological interest in metal complexes for various dielectric media. The results show that Δ G ex is sensitive to the dielectric constant of the environment and that a low dielectric medium favors the inner-sphere binding of protein ligands, especially negatively charged amino acid residues, to the metal.