Calculated hydration free energies, versus error with single-conformation schemes. Calculated hydration free energies are plotted, versus the error from these values when using different choices of single-conformations for computing hydration free energies. The different schemes are as follows: BestG, the conformation resulting in the most favorable hydration free energy estimate; WorstG, the conformation resulting in the least favorable hydration free energy estimate; BestVac, the conformation with the lowest potential energy in vacuum; and BestSolv, the conformation with the lowest potential energy in solvent. The γ = 0 line indicates exact agreement between calculated single-conformation hydration free energies and calculated hydration free energies. Values below the line overestimate the affinity for water; those above the line underestimate the affinity for water.