Using DFT methods for the prediction of the structure and energetics of metal‐binding sites in metalloproteins

In recent years, density functional theory (DFT) methods have been successfully applied in the area of quantum bioinorganic chemistry. Often, they are the only methods of choice for the calculations of the accurate molecular properties of model systems containing transition metal(s) (TMs) and up to additional 50 atoms. In our contribution, we present an example of the application of DFT methods for the quantitative estimates of complexation energies of several TM ions (Co2+, Ni2+, Cu2+, Zn2+, Cd2+, and Hg2+) in general metal‐binding sites in metalloproteins. Our approach is based on the calculations of the interaction energies of model functional groups with the TM ions, defined as the substitution energy of single water molecule from the coordination sphere of a metal ion, and the evaluation of the cooperative effect, defined as the nonadditive part of the substitution of the second water molecule. It is demonstrated that it is possible to derive complexation energy of the given TM ion in “per‐substituted” [MXn]2+ site by combining the above two contributions with 5‐ to 15‐kcal/mol accuracy and thus a number of metal‐binding sites in metalloproteins can be readily scanned for their specificity toward the studied TM ions.