We then assessed whether thorough conformation sampling of the ligands improved the deformation energy and thus the ∆H in a virtual screening setting. As illustrated in Fig- , there is no benefit from performing laborious ligand conformational sampling with Macromodel and then PM6/COSMO geometry optimization. We can still compute a good ∆H approximation (∆H*) by using the minimum molecular energy of the same docking poses that we optimized and rescored with PM6/COSMO. This conclusion is seconded by one-way ANOVA of these three alternative ways to compute the ∆H, which yielded a P-value of 0.9917 (the differences between the means are not statistically significant).