Theoretical Study of Binding of Hydrated Zn(II) and Mg(II) Cations to 5‘-Guanosine Monophosphate. Toward Polarizable Molecular Mechanics for DNA and RNA

SIBFA polarizable molecular mechanics (PMM) and quantum-chemical (ab initio Hartree−Fock and DFT) computations are performed on the binding of hydrated Zn(II) and Mg(II) cations to 5‘-guanosine monophosphate, a basic building block of nucleic acids, probing both C2‘ endo and C3‘ endo conformations. The interaction energies of the hydrates, ΔE int, are compared in three distinct arrangements: (A) simultaneous binding of the dication to both O1 and N7, (B) direct binding to O1 and through-water binding to N7, and conversely, (C) through-water binding to O1 and direct binding to N7. With a C2‘ endo sugar, bidentate complex A has a marginally more favorable ΔE int than directly bound phosphate complex B. With a C3‘ endo sugar, A has a distinctly more favorable ΔE int value than B and C. ΔE int(SIBFA) has values that are intermediate between those of ΔE(DFT) obtained using the 6-311G** and LACVP** basis sets. Zn(II) complexes are favored over the corresponding Mg(II) ones by the dispersion and charge-transfer terms, while the sum of electrostatic and short-range repulsion favors the Mg(II) complexes. The different balance of individual contributions is responsible for the distinct biological and biochemical roles of the two cations. Additional comparisons of PMM with quantum-chemical computations are performed for the solvation energy, ΔG solv, computed with a continuum reaction field procedure integrated in SIBFA, and for the internal conformational energy of the nucleotide in the investigated complexes. The SIBFA and quantum-chemical results are also compared with polarizable and nonpolarizable force fields currently available in the AMBER molecular modeling code.