A weakness, however, is that when end states differ and the conformational change is not sampled during NEQ switching, dissipation can be large and a slow switching rate or numerous transitions may be required to obtain a converged free energy difference. In the case of Val111 sampling in 3-iodotoluene, we saw that this can be very limiting. Possibly separation of states approaches can help with this issue, 82 e.g. having the side chain restrained during the calculations and accounting for it later. This how-ever, creates its own problems in some cases.