Formation of a Thymine-HgII-Thymine Metal-Mediated DNA Base Pair: Proposal and Theoretical Calculation of the Reaction Pathway

A reaction mechanism that describes the substitution of two imino protons in a thymine:thymine (T:T) mismatched DNA base pair with a Hg-II ion, which results in the formation of a (T)N3-Hg-II-N3(T) metal-mediated base pair was proposed and calculated. The mechanism assumes two key steps: The formation of the first Hg(II)N3(T) bond is triggered by deprotonation of the imino N3 atom in thymine with a hydroxo ligand on the Hg-II ion. The formation of the second Hg(II)N3(T) bond proceeds through water-assisted tautomerization of the remaining, metal-nonbonded thymine base or through thymine deprotonation with a hydroxo ligand of the Hg-II ion already coordinated to the thymine base. The thermodynamic parameters G(R)=-9.5kcalmol(-1), H-R=-4.7kcalmol(-1), and S-R=16.0calmol(-1)K(-1) calculated with the ONIOM (B3LYP:BP86) method for the reaction agreed well with the isothermal titration calorimetric (ITC) measurements by Torigoe etal. [H. Torigoe, A. Ono, T. Kozasa, Chem. Eur. J.2010, 16, 13218-13225]. The peculiar positive reaction entropy measured previously was due to both dehydration of the metal and the change in chemical bonding. The mercury reactant in the theoretical model contained one hydroxo ligand in accord with the experimental pK(a)value of 3.6 known for an aqua ligand of a Hg-II center. The chemical modification of T:T mismatched to the T-Hg-II-T metal-mediated base pair was modeled for the middle base pair within a trinucleotide B-DNA duplex, which ensured complete dehydration of the Hg-II ion during the reaction.