Optimized Halogen Atomic Radii for PBSA Calculations Using Off-Center Point Charges

In force-field methods, the usage of off-center point charges, also called extra points (EPs), is a common strategy to tackle the anisotropy of the electrostatic potential of covalently bonded halogens (X), thus allowing the description of halogen bonds (XBs) at the molecular mechanics/molecular dynamics (MM/MD) level. Diverse EP implementations exist in the literature differing on the charge sets and/or the X–EP distances. Poisson–Boltzmann and surface area (PBSA) calculations can be used to obtain solvation free energies (ΔGsolv) of small molecules, often to compute binding free energies (ΔGbind) at the MM-PBSA level. This method depends, among other parameters, on the empirical assignment of atomic radii (PB radii). Given the multiplicity of off-center point-charge models and the lack of specific PB radii for halogens compatible with such implementations, in this work, we assessed the performance of PBSA calculations for the estimation of ΔGsolv values in water (ΔGhyd), also conducting an optimization of the halogen PB radii (Cl, Br, and I) for each EP model. We not only expand the usage of EP models in the scope of the general AMBER force field (GAFF) but also provide the first optimized halogen PB radii in the context of the CHARMM general force field (CGenFF), thus contributing to improving the description of halogenated compounds in PBSA calculations.