If the rotamer population is not sampled correctly in the end states, the results will be inaccurate or imprecise, and a bimodal distribution can in some cases be a warning sign that sampling might be complex or slow. Restraining the Ile78 side chain resulted in a unimodal work distribution (SI Figure ) which further supports our findings that different rotamers of Ile78 in the B state led to a bimodal work distribution in the reverse transitions. The situation could have been worse if the noninteracting state did not already spend time sampling both rotamers and if the reorientation occurred on longer timescales. If a conformational transition is truly needed on binding then instead of having a bimodal distribution the final distribution might be unimodal, but wrong, as discussed in Sec. 4.4 and in Sec. 5.3.2.