Factors altering the affinity of protein–ligand binding in an external electrostatic field

• Factors influencing protein–ligand binding affinity under applied Eext are proposed.
• Under applied Eext, the waters neighboring ligand will be repelled from the ligand.
• Binding affinity decreases due to the repulsion from neighboring water molecules.
• Under Eext, the electric force on the ligand from water is contributed by Pprotein.
• Pprotein is in the region occupied by the protein and is proportional to −Eext.

The effects of an external electric field on the binding affinity for protein–ligand complexes was determined by applying electric field Eext to a water cluster containing two electric dipoles separated by a certain distance. The mean forces on these two dipoles were computed from the trajectories of molecular dynamics simulations. The results showed that the mean attractive force and the binding affinity between these two dipoles decreased with increasing Eext. Two factors governing the effects of Eext on the binding affinity of protein–ligand interactions were proposed. (1) When Eext is applied to a water cluster containing protein–ligand complexes, the water molecules neighboring ligand will be repelled from the ligand; the mean van der Waals repulsive force exerted on the ligand by these water molecules would decrease, leading to a decrease in the binding affinity between the protein and the ligand. (2) The mean electrostatic force exerted on the ligand by the water molecules polarized by Eext is thought to result from the dielectric polarization (Pprotein) in the region occupied by the protein, where Pprotein is proportional to −Eext.