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 hydrophobi c groups. The hydrophilic protein residues tend to bind directly to the met al (inner-sphere mode), instead of indirectly via a metal-bound water molec ule (inner-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 employ ed to compute the free energy (Delta G(ex)) of the exchange reaction betwee n a metal-bound water molecule and ligands of biological interest in metal complexes for various dielectric media. The results show that Delta G(ex) i s sensitive to the dielectric constant of the environment and that a low di electric medium favors the inner-sphere binding of protein ligands, especia lly negatively charged amino acid residues, to the metal.