Particularly, we have shown that NCMC can greatly enhance move acceptance for exploring ligand binding modes by allowing for relaxation during attempts. NCMC also allows dramatically faster sampling than standard MD because of its ability to cross steric barriers; advantages over standard MC are less clear but grow with the size of the ligand relative to the amount of space it has in the binding site. The generality of this method is particularly appealing. We did not use any prior information about the binding modes in generating our move proposals, which involve random rigid-body rotations, thus this type of move shows promise in broadly sampling different potential binding modes without any prior knowledge. Extensions of this approach however, could potentially make use of other information-for instance from docking-to perform guided rotations targeting specific binding modes. Although NCMC rotational moves can help sample potentially slow binding mode transitions, there are some factors which can pose challenges for this approach. The acceptance rate will likely decrease as the ligand size grows, since a larger percentage of possible random rotations will lead to particularly significant clashes that cannot relax in the span of the move, and favorable binding modes will become correspondingly harder to find by random exploration. Additionally, rotational moves alone will not cover all binding mode possibilities in some cases, but the addition of other Monte Carlo moves (such as translation) could perhaps help address this. Also, rigid body random rotations of a ligand will likely not be as effective for flexible ligands, whose binding modes can be dependent on changes to the internal degrees of freedom such as torsional rotations.