When employing topology schemes such as the hybrid single-dual introduced by Jiang et al. or our TIES modified dual topology scheme, there is an additional variable involved: the number of atoms in the alchemical region. Hereafter, we will refer to it as the size of the alchemical region. We have shown previously that the precision of our TIES results is inversely proportional to this quantity due to slow convergence. In addition, if the alchemical region so defined includes charged groups, then the error bars become even larger.