To assess whether the REST2 protocol and simulation length is sufficient, we calculated the standard deviation from trajectory splitting for each NOE distance. The root-mean-square of the standard deviations over all NOE distances of each compound are reported in Table to obtain an impression of the expected sampling uncertainties, indicating that the simulations are converged. Of course, it cannot be excluded that conformational changes may occur, which are slower than the chosen simulation length or separated by energy barriers that are too high for the chosen sampling-enhancement scheme. The latter point was illustrated by the example of lorlatinib in Figure in the Supporting Information, where the correct conformer was only sampled when incorporating bond-angle terms in the REST2 protocol.