Issue 21, 2020

On the polarization of ligands by proteins

Abstract

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). Calculations were performed both with and without implicit solvent based on the domain decomposition Conductor-like Screening Model. 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−1 at 9 Å and 1 kcal mol−1 at 12 Å. Compared to these embedding field charges, implicit solvent has a relatively minor effect on ligand polarization. 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.

Graphical abstract: On the polarization of ligands by proteins

Supplementary files

Article information

Article type
Paper
Submitted
22 yan 2020
Accepted
01 may 2020
First published
18 may 2020
This article is Open Access
Creative Commons BY license

Phys. Chem. Chem. Phys., 2020,22, 12044-12057

On the polarization of ligands by proteins

S. Y. Willow, B. Xie, J. Lawrence, R. S. Eisenberg and D. D. L. Minh, Phys. Chem. Chem. Phys., 2020, 22, 12044 DOI: 10.1039/D0CP00376J

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