Automated parameterization of quantum-mechanically derived force-fields including explicit sigma holes: A pathway to energetic and structural features of halogen bonds in gas and condensed phase.

In classical molecular dynamics, general purpose atomistic force-fields (FFs) often deliver inaccurate results when dealing with halogen bonds (XBs), notwithstanding their crucial role in many fields of science, ranging from material design to drug development. Given the large dimensions of the systems of interest, it would be therefore desirable to increase the FF accuracy maintaining the simplicity of the standard Lennard-Jones (LJ) plus point charge description to avoid an excessive computational cost. A simple yet effective strategy consists in introducing a number of virtual sites able to mimic the so-called "explicit σ-hole." In this work, we present an automated FF parameterization strategy based on a global optimization of both LJ and charge parameters with respect to accurate quantum mechanical data, purposely computed for the system under investigation. As a test case, we report on two homologue series, characterized either by weak or strong XBs, namely, the di-halogenated methanes and the mono-, di-, and tri-substituted acetonitriles, taking into consideration Cl, Br, and I substituents. The resulting quantum mechanically derived FFs are validated for each compound in the gas and in the condensed phase by comparing them to general purpose and specific FFs without virtual sites and to highly accurate reference quantum mechanical data. The results strongly support the adoption of the specific FFs with virtual sites, which overcome the other investigated models in representing both gas phase energetics and the structural patterns of the liquid phase structure related to the presence of XBs.