  Recent predictions of absolute binding free energies of host-guest complexes
in aqueous solution using electronic structure theory have been encouraging for
some systems, while other systems remain problematic for others. In paper I
summarize some of the many factors that could easily contribute 1-3 kcal/mol
errors at 298 K: three-body dispersion effects, molecular symmetry,
anharmonicity, spurious imaginary frequencies, insufficient conformational
sampling, wrong or changing ionization states, errors in the solvation free
energy of ions, and explicit solvent (and ion) effects that are not
well-represented by continuum models. While I focus on binding free energies in
aqueous solution the approach also applies (with minor adjustments) to any free
energy difference such as conformational or reaction free energy differences or
activation free energies in any solvent.
