A quantum-mechanical study of metal binding sites in zinc finger structures

Abstract

Density functional theory (DFT) methods were used to calculate geometric and electronic properties for the metal binding sites belonging to three distinct zinc finger families, as well as for that of a binuclear M 2Cys 6 sequence. DFT-derived structural parameters such as bond distances and angles for Zn II and Cd II binding sites were in agreement with experimental values obtained from EXAFS, X-ray crystallography, and multidimensional NMR spectroscopy for related systems. Calculations of the electronic properties of these peptides indicate that the chelating residues alone are responsible for the majority of the free energy of metal binding, with only a small contribution attributable to neighboring residues. Our calculations also predict that the binding affinity for a given metal ion increases with the number of thiolate ligands, and is consistent with experimental observations of the relative metal ion affinities for peptides from different zinc finger families. For all zinc finger families, calculated ionization potentials for Cd II-bound peptides were larger than those for the Zn II-bound species, leading to the prediction of faster redox reaction rates for the latter. We discuss the implications of these results for the structure and function of zinc fingers, as well as for the design of compounds affecting their chemical integrity.