Tackling Halogenated Species with PBSA: Effect of Emulating the σ-hole

To model halogen-bond phenomena using classical force fields, an extra point (EP) of charge is frequently introduced at a given distance from the halogen (X) to emulate the σ-hole. The resulting molecular dynamics (MD) trajectories can be used in subsequent molecular mechanics (MM) combined with Poisson–Boltzmann and surface area calculations (PBSA) to estimate protein–ligand binding free energies (ΔGbind). While EP addition improves the MM/MD description of halogen-containing systems, its effect on the calculation of solvation free energies (ΔGsolv) using the PBSA approach is yet to be assessed. As the PBSA calculations depend, among other parameters, on the empirical assignment of radii (PB radii), a problematic issue arises, since standard halogen radii are smaller than the typical X···EP distances, thus placing the EP within the solvent dielectric. Herein, we took a common literature EP parametrization scheme, which uses X···EP = Rmin and RESP charges in the context of GAFF, and performed a comprehens...