The effect of metal binding to the N7 site of purine nucleotides on their structure, energy, and involvement in base pairing

Direct binding of hydrated zinc and magnesium group divalent cations to the N7 position of purine nucleotides has been investigated by ab initio quantum chemical calculations. The sugar-phosphate backbone provides significant screening of the charge of the metal while the backbone geometry can be affected by the cation, Polarized water molecules of the cation hydration shell form very strong hydrogen bond bridges between the cation and the anionic oxygen atoms of the phosphate group, Weaker hydrogen bonds are formed between the cation hydration shell and the exocyclic purine X6 atoms. The cation binding to N7 of adenosine monophosphate forces the adenine amino group to be nonplanar, Its nitrogen atom serves as an H-acceptor for a water molecule from the cation hydration shell while the amino-group hydrogen atom adjacent to N7 sharply deviates from the adenine plane. This hydrogen is capable of forming out-of-plane hydrogen bonds with a neighboring base pair or a water molecule in DNA, Cation binding to N7 does not lead to any major changes in the geometry of the base pairing, However, the stability of the base pairing can be increased by polarization of the purine base by the cation and by long-range electrostatic attraction between the hydrated cation and the other nucleobase. The stability of guanine-cytosine Watson-Crick base pairing is enhanced by the polarization mechanism while the stability of the adenine-thymine Watson-Crick base pair is enhanced by the electrostatic effects. The guanine-guanine reverse-Hoogsteen base pairing is stabilized by both contributions while the adenine-adenine reverse-Hodgsteen system is not influenced by the cation. Binding of a cation to the N7 of guanine promotes transfer of its H1 proton to the N3 acceptor site of cytosine. However, the negatively charged backbone exerts a significant screening effect on this potentially mutagenic process, and the probability of such a proton transfer in DNA should be only moderately enhanced by a cation binding, The complexes studied are characterized by highly nonadditive molecular interactions. This implies limited applicability of pair additive potentials to describe the direct binding of divalent cations to nucleobases in DNA.