• density functional theory;
  • QM/MM;
  • free energy calculation;
  • theory of energy representation;
  • radical scavenger


The anionic derivative of the pharmaceutical compound 3-methyl-1-phenyl-2-pyrazolin-5-one (MCI-186) is known to deactivate the free radicals in biological systems by donating its excess electron. For the purpose to investigate the mechanism that the MCI-186 anion exhibits the antioxidative activity in aqueous solutions, we have performed a series of quantum mechanical/molecular mechanical (QM/MM) simulations based on the density functional theory in combination with the theory of energy representation (QM/MM-ER). For the computational convenience, MCI-186 has been modeled by 1,3-dimethyl-2-pyrazolin-5-one (DMP) by substituting the phenyl group in MCI-186 by a methyl one. We have applied the QM/MM-ER approach to compute free energy change δGaq associated with the electron detachment from DMP anion in water. To make comparisons, we have also performed the simulations for a natural radical scavenger, ascorbic acid modeled by 3,4-dihydroxy-furan-2-one (DHF). In the QM/MM-ER approach, the distribution functions of the solute–solvent interaction energy, which serve as fundamental variables to describe the free energy, are to be constructed with the QM/MM force field. The free energy changes δGaq were computed as 99.1, 108.3 kcal/mol for DMP and DHF anions, respectively, whereas that for hydroxyl anion OH taken as a reference system was evaluated as 138.9 kcal/mol. Thus, it was revealed that the free energies δGaq for DMP and DHF anions are much smaller than that for hydroxyl anion, which directly indicates the high activities of the molecules as electron donors. We found that the small δGaq values can be mainly attributed to the small values in the absolutes of the solvation free energies. The fractional charge analyses provided the evidence that the delocalization of the excess charge on the solute gives rise to the destabilization of these radical scavengers in the solute–solvent interaction. © 2010 Wiley Periodicals, Inc. Int J Quantum Chem, 2010