Tetrahedral vs octahedral zinc complexes with ligands of biological interest: A DFT/CDM study

To elucidate the most preferable, ground-state coordination geometry for zinc complexes in a protein environment, the free energies of isomerization between hexa- and tetracoordinated structures containing Zn2+ bound to water and ligands of biological interest were evaluated. Density functional theory using the 6-313-++G-(2d,2p) basis set was employed in calculating isomerization free energies in the gas phase, while continuum dielectric theory was used to compute solvation free energies of the zinc clusters in different dielectric media. The results show that the lowest-energy ground-state coordination number of zinc bound to one acidic or two or more neutral protein ligands is 4. The observed decrease in the coordination number of zinc upon protein binding reflects primarily the requirements of the metal and ligands, rather than the constraints of the protein matrix on the metal. Our finding that the tetrahedral zinc complexes in protein cavities generally represent the optimal, least strained structures among various zinc polyhedra may explain why four-coordinate zinc is chosen to play a structural role in zinc fingers and enzymes.