Compound 1 adapts its conformation to the binding guest via an induced fit mechanism. In Fig. we show the two main conformations of macrocycle 1. The two cage structures can be distinguished by the value of any of the three angles α involving equivalent phenyl carbons (in orange color) on the three sides of the cage. In the most symmetric conformer a (on the left in Figure ) the three angles are in the range 55-70 degrees, while in the twisted structure b (on the right in Figure ), one of the angles is around 45 degrees. One of the two rapidly exchanging conformations is in general selected when 1 bind specifically to quaternary ammonium cations. We performed two HREM simulations, each lasting 16 ns, of the compound 1 in vacuo at 300 K. In both cases, due to the relatively low conformational barriers between the two structure (see Figure , the scaling protocol was given by Eq. 3. In the other, we used the acceptance ratio balancing algorithm of Eq. 4 starting from the default scaling protocol of Eq. 3. In Table , we report the acceptance probability (in percent) for the HREM simulations with and without P acc balancing. In the standard HREM simulation, with the default scaling Eq. 3, P acc balance is poor, with P acc at the end of the ladder being more than one order of magnitude larger with respect to exchanges 1 ↔ 2 involving the target state. In the adaptive HREM simulation, excellent balancing was reached after ten iteration of Eq. 4 (taken at regular interval in the first 1.6 ns simulation) at the expense of the mean acceptance ratio which dropped from 14.4% to 11.2 %.