  Although ligand-binding sites in many proteins contain a high number density
of charged side chains that can polarize small organic molecules and influence
binding, the magnitude of this effect has not been studied in many systems.
Here, we use a quantum mechanics/molecular mechanics (QM/MM) approach in which
the ligand is the QM region to compute the ligand polarization energy of 286
protein-ligand complexes from the PDBBind Core Set (release 2016). We observe
that the ligand polarization energy is linearly correlated with the magnitude
of the electric field acting on the ligand, the magnitude of the induced dipole
moment, and the classical polarization energy. The influence of protein and
cation charges on the ligand polarization diminishes with the distance and is
below 2 kcal/mol at 9 $\unicode{x212B}$ and 1 kcal/mol at 12 $\unicode{x212B}$.
Considering both polarization and solvation appears essential to computing
negative binding energies in some crystallographic complexes. Solvation, but
not polarization, is essential for achieving moderate correlation with
experimental binding free energies.
