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.
Highlights
Noncovalent binding to proteins is a key mechanism by which small organic molecules interact with biological systems
Cho et al.[16] demonstrated the importance of embedding by evaluating the ability of multiple docking schemes to recapitulate ligand binding poses in 40 diverse complexes. They found that assigning ligand charges using a quantum mechanics/molecular mechanics (QM/MM) method with electrostatic embedding was generally more successful than a gas-phase Quantum mechanics (QM) method without embedding
Using OpenMM 7.3.1,41 complexes in OBC229 generalized Born/surface area implicit solvent were minimized with heavy atom restraints of 2 kcal molÀ1 ÅÀ2 towards crystallographic positions until energies converged within 0.24 kcal molÀ1
Summary
Noncovalent binding to proteins is a key mechanism by which small organic molecules (ligands) interact with biological systems. Cho et al.[16] demonstrated the importance of embedding by evaluating the ability of multiple docking schemes to recapitulate ligand binding poses in 40 diverse complexes. They found that assigning ligand charges using a QM/MM method with electrostatic embedding was generally more successful than a gas-phase QM method without embedding. The extent of ligand polarization by the protein environment has not been compared to the extent of ligand polarization by solvent We address this knowledge gap by calculating the ligand polarization energy, with and without a continuum dielectric implicit solvent model, for 286 protein– ligand complexes from the PDBBind Core Set (release 2016).[25] The PDBBind is a comprehensive database of complexes for which both Protein Data Bank crystal structures and binding affinity data are available. Calculations with implicit solvent allow us to compare the magnitude of ligand polarization by the protein and the solvent
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Free) 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
