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Halogen atoms are widely used in drug molecules to improve their binding affinity for the receptor proteins. Many of the examples involve “halogen bonding” between the molecule and the binding site, which is a directional interaction between a halogen atom and a nucleophilic atom. Such an interaction is induced by an electron cloud shift of the halogen atom toward its covalently bonded neighbor to form the σ-bond, leaving a small electrostatic positive region opposite to the bond called the “σ-hole.” To mimic the effect of the σ-hole in the CHARMM non-polarizable force field, recently CGenFF added a positively charged massless particle to halogen atoms, positioned at the opposite side of the carbon–halogen bond. This particle is referred to as a lone pair (LP) particle because it uses the lone pair implementation in the CHARMM force field. Here, we have added support for LP particles to ffTK, an automated force field parameterization toolkit widely distributed as a plugin to the molecular visualization software VMD. We demonstrate the updated optimization process using an example halogenated drug molecule, AT130, which is a capsid assembly modulator targeting the hepatitis B virus. Our results indicate that parameterization with the LP particle significantly improves the accuracy of the electrostatic response of the molecule, especially around the halogen atom. Although the inclusion of the LP particle does not produce a prominent effect on the interactions between the molecule and its target protein, the protein–ligand binding performance is greatly improved by optimization of the parameters.

Single-step free energy perturbation (sFEP) has often been proposed as an efficient tool for a quick free energy scan due to its straightforward protocol and the ability to recycle an existing molecular dynamics trajectory for free energy calculations. Although sFEP is expected to fail when the sampling of a system is inefficient, it is often expected to hold for an alchemical transformation between ligands with a moderate difference in their sizes, e.g., transforming a benzene into an ethylbenzene. Yet, exceptions were observed in calculations for anisole and methylaniline, which have similar physical sizes as ethylbenzene. In this study, we show that such exceptions arise from the sampling inefficiency on an unexpected rigid degree of freedom, namely, the bond angle θ. The distributions of θ differ dramatically between two end states of a sFEP calculation, i.e., the conformation of the ligand changes significantly during the alchemical transformation process. Our investigation also reveals the interrelation between the ligand conformation and the intramolecular nonbonded interactions. This knowledge suggests a best combination of the ghost ligand potential and the dual topology setting, which improves the accuracy in a single reference sFEP calculation by bringing down its error from around 5kBT to kBT.