Notwithstanding, as seen in Figure , this did have little effect on the overall performance of PM6/COSMO in virtual screening on the ACHE dataset. However, one direct side-effect of excluding the protein atoms from the SQM part is that many optimized poses have artificially high or low interaction energy, like compound BDB50322767, which is nicely illustrated by the distribution of interaction energies in the three optimization schemes (Figure ). Yet the inclusion of protein atoms in the SQM region comes with a heavy computational cost, which increases almost exponentially with the size of the SQM region (Figure ). There-fore, we decided to optimize only the ligand with PM6/COSMO in our scoring protocol. As a remedy for the extreme interaction energies, we tried to discard poses that had Eint more than 8 standard deviations from the mean Eint of each structural variant, but as shown in Figure , discarding docking poses compromises the predictive accuracy of PM6/COSMO.