QM and QM/MM umbrella sampling MD study of the formation of Hg(II)–thymine bond: Model for evaluation of the reaction energy profiles in solutions with constant pH

The formation of the Hg–N3(T) bond between the 1‐methylthymine (T) molecule and the hydrated Hg 2+ cation was explored with the combined quantum mechanics/molecular mechanics (QM/MM) method including Free Energy Perturbation corrections. The thermodynamic properties were determined in the whole pH range, when these systems were explicitly investigated and considered as the QM part: (1) T + [Hg(H 2 O) 6 ] 2+ , (2) T + [Hg(H 2 O) 5 (OH)] + , (3) T + Hg(H 2 O) 4 (OH) 2 , and (4) N3‐deprotonated T + Hg(H 2 O) 4 (OH) 2 . The MM part contained only solvent molecules and counterions. As a result, the dependence of Gibbs‐Alberty reaction free energy on pH was obtained along the reaction coordinate. We found that an endoergic reaction in acidic condition up to pH < 4–5 becomes exoergic for a higher pH corresponding to neutral and basic solutions. The migration of the Hg 2+ cation between N3 and O4/2 positions in dependence on pH is discussed as well. For the verification, DFT calculations of stationary points were performed confirming the qualitative trends of QM/MM MD simulations and NMR parameters were determined for them.