A reaction mechanism that describes the substitution of two imino protons in a thymine:thymine (T:T) mismatched DNA base pair with a HgII ion, which results in the formation of a (T)N3-HgII-N3(T) metal-mediated base pair was proposed and calculated. The mechanism assumes two key steps: The formation of the first HgII-N3(T) bond is triggered by deprotonation of the imino N3 atom in thymine with a hydroxo ligand on the HgII ion. The formation of the second HgII-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 HgII ion already coordinated to the thymine base. The thermodynamic parameters ΔGR=-9.5 kcal mol-1, ΔHR=-4.7 kcal mol-1, and ΔSR=16.0 cal mol-1 K -1 calculated with the ONIOM (B3LYP:BP86) method for the reaction agreed well with the isothermal titration calorimetric (ITC) measurements by Torigoe et al. [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 pKa value of 3.6 known for an aqua ligand of a HgII center. The chemical modification of T:T mismatched to the T-HgII-T metal-mediated base pair was modeled for the middle base pair within a trinucleotide B-DNA duplex, which ensured complete dehydration of the HgII ion during the reaction. The bridging mercury within DNA: The formation of the first HgII-T bond during the reaction mechanism for the generation of a T-HgII-T metal-mediated base pair (see scheme; T=thymine) is triggered by a hydroxo ligand on the HgII ion. The second linkage, as the rate-limiting step, proceeds through water-assisted tautomerization of the thymine base. A positive ΔSR value was due to both dehydration of the HgII ion and the change in chemical bonding during the reaction.
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