A snapshot of IBU in the down orientation is shown in Figure . Our results presented in Table represent a combined 2 µs simulation time for each investigated guest molecule and hundreds of thousands of MM/GBSA calculations. To investigate the precision of the obtained results and to study whether the number of samples used can be reduced without compromising the precision, we performed bootstrapping with replacement on subsets of the results obtained from the simulations with probabilities for selecting a specific DS taken from the relative abundances in Figure . The resulting standard error of the mean computed free energies of binding presented in Figure shows how much the computed mean can be expected to change if we were to randomly construct a new ensemble for a specified sample size. We observe that the standard errors decline rapidly towards 0.2 kcal/mol for smaller sample sizes (< 25) but then becomes relatively flat for larger sample sizes (> 50). We have