Outer-Shell and Inner-Shell Coordination of Phosphate Group to Hydrated Metal Ions (Mg²⁺, Cu²⁺, Zn²⁺, Cd²⁺) in the Presence and Absence of Nucleobase. The Role of Nonelectrostatic Effects

Inner-shell binding of selected hydrated metal ions (Mg²⁺, Cu²⁺, Zn²⁺, and Cd²⁺) to the guanine N7 position accompanied with outer- and inner-shell binding to an anionic phosphate group is investigated using quantum chemical approaches. The study is focused on the mutual interplay between the metal−phosphate and metal-nucleobase binding and the role of nonelectrostatic effects in the metal binding as these contributions are not included in conventional empirical force fields. The analysis of the equilibrium structures and the energy decompositions reveal that these effects substantially contribute to the differences in the coordination behavior of the studied metal ions. The Zn²⁺ and Cd²⁺ cations show a clear preference to bind to N7 of guanine compared to Mg²⁺. The selectivity is of ca. 3−4 kcal·mol^-1 on the energy scale. This energy difference is sufficient to provide enough binding selectivity in the condensed phase where the dominant pair electrostatic terms (ion−ion, molecule−ion) are attenuated. Cu²⁺ shows even stronger relative preference for N7 binding and it has also different coordination requirements. The nucleobase N7 metal binding causes ca. 20−30 kcal·mol^-1 destabilization of the metal−phosphate outer-shell binding, entirely due to nonelectrostatic effects. The calculations were done with the Becke3LYP DFT method and extended basis set of atomic orbitals for energy evaluations. This technique provides a very accurate description of metal cation containing clusters. It is demonstrated for Mg²⁺ systems using reference RI-MP2/TZVPP calculations showing excellent agreement with the DFT approach regarding both molecular structures and energies. Most systems were also optimized with the HF/6-31G* method supplemented by MP2 single point energy evaluations. The later method was utilized in many recent studies of cation binding to nucleic acids and is shown here to provide meaningful results. Validity of the conclusions based on calculations utilizing the gas-phase cluster model is further verified by additional calculations of the solvation effects. The present study reveals important qualitative aspects of selective metal binding to nucleic acids, provides useful comparison of different computational methods, and furnishes reference data for verification and parametrization of other computational methods including force fields.