Minimizations were carried out using the same set-up as for the MD simulations. To optimize structures, the L-BFGS algorithm was used. RDKit was employed to generate the initial KDG conformers and MDTraj (version 1.9.7) was used to prune the minimized conformations based on their heavy-atom RMSD. The selection of a suitable RMSD threshold is not straightforward, as the RMSD metric is sensitive to the size of a molecule . We have therefore chosen different thresholds for different molecules, which are specified in each section of the Methods section. Free energies were calculated using normal-mode analysis according to the quasi-RRHO algorithm proposed by Grimme . Conformers that led to imaginary frequencies were minimized further for up to 100 repeats. Note that some of the minimization did not converge or led to imaginary frequencies in the free-energy calculation. In both cases, the energy was set to infinity, and the conformers were ignored for the follow-up comparisons. The minimization in vacuum and using the GB-Neck2 implicit solvent model were carried out the same way starting from the same set of random conformers.