Although we are aware that the use of restraints is not a good general solution to inadequate side chain rotamer sampling, we think that it helps illustrate a potential pitfall of these approaches. Particularly, restraining the side chains gives the same outcome one might get in a shorter simulation, or a simulation where the environment is more sterically constrained (in which the side chain might not switch rotamers at all). In such cases, one might see "good overlap" in the non-equilibrium work distributions but only because the simulations missed an important motion that needs to be sampled. 5.4. Summary of the T4 lysozyme system. In the T4 lysozyme cases examined, convergence of the ∆G estimate was challenging due to side chain rotamer sampling. Slow side chain rearrangements, like Val111 in the 3iodotoluene case, proved to be very challenging both in EQ and NEQ approaches. The length of NEQ transitions became very important here. Sufficient sampling of faster side chain-rearrangements upon binding, like Ile78 in the toluene system, was achieved by running longer/many NEQ transitions and long equi-libration in the equilibrium FEC. In principle this could be true for slower rearrangements too, but in some cases the relevant motions can take nanoseconds to hundreds of nanoseconds for a single transition, making it less desirable to simply run longer simulations. In the NEQ approach, sampling problems were detectable from work value trends and their correlation with structural degrees of freedom in equilibrium snapshots they were derived from. Here, we restrain the dihedral angles of the side chains to work around the issues but our findings suggest that better and more robust methods are necessary to solve the problem.