In this system, sampling of different rotamers of Ile78 led to a bimodal work distribution in the direction of restoring the ligand-protein interactions (the direction we call B2A, as our B state is the noninteracting state), and this was especially common for fast transitions (Figure ). While a bimodal distribution of work values itself does not necessarily pose a prob- lem, it can pose a problem when it results from drawing from an incorrect or biased distribution of states at the end states -such as when a slow conformational transition is inadequately sampled for one or both end states -or when it results from transitions which are too fast to sample an important conformational change.