To test the effect of the additional off-center point charges, the liquid properties for the benchmark test set were also calculated in the absence of extra sites. This led to a general worsening of the results with the MUEs becoming 0.023 g/cm 3 , 0.85 kcal/mol and 1.51 kcal/mol in the density, the heat of vaporization and free energy of hydration respectively (Figure ). As expected, since it is governed mostly by Lennard-Jones interactions, the error in the density remained approximately constant. However, the decline in accuracy of the other properties indicates that modelling of anisotropy in electron density is required to accurately describe intermolecular interactions. This is consistent with the increasing use of virtual sites in multiple FFs. While there is no unique way to derive virtual site parameters, it would seem that deriving the parameters to minimize the error in ESP for an individual atom is effective. Figure compares the ESP error around atoms before and after the addition of virtual sites. While some residual error is to be expected given the simplicity of the FF functional form, the errors on these atoms displaying highly anisotropic electron density is now much closer to, and in many case below, the average ESP error across every atom in the benchmark set. Figure shows a selection of molecules from the test set that required virtual sites, the rest of the derived site positions and corresponding charges can also be found in the Supporting Information. Here we can see that the derived positions are chemically intuitive, with σ-holes and lone-pairs well-represented. In total 50 of the 109 molecules in the test set required at least one virtual site, and on average a molecule whose functional group ESP error is initially above the chosen threshold requires 2.1 virtual sites. While this is more than is typical in molecular mechanics simulations, the computational cost of virtual sites in an MD simulation is small. Furthermore, QUBEKit substantially simplifies the process for the user by deriving the virtual site parameters from QM and writing them to simulation-ready input files.