The calculation of free energy changes is fundamental for the thermodynamic characterization of reaction pathways and chemical equilibria. The conventional approaches, free energy perturbation (FEP) and thermodynamic integration (TI), were predicated on Kirkwood's introduction of the continuous coupling parameter in his integral equation studies of fluid systems. Later work by Zwanzig further advanced the mathematical formalism of free energy perturbation theory, and this, in conjunction with molecular dynamics and Monte Carlo sampling techniques, has become a principal approach for calculating free-energy differences. Some applications have included computation of relative free energies of solvation, relative pK_a values, medium-effects on conformational eauilibria. host— suest binding affinities.
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