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.
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