Figure shows a cartoon of how these NCMC moves can work for exploring ligand binding modes. The ligand starts fully interacting (Figure ) and its interactions with the rest of the system are slowly turned off through alchemical coupling over a series of NCMC steps (Figure )). When the ligand is fully non-interacting, a random rotation (see Section 2.1.4) around the ligand's center of mass is performed (Figure ). Then the ligand's interactions are subsequently turned back on until it is once again fully interacting, potentially allowing it to find an alternate favorable orientation in the binding site (Figure )). We then accept or reject the move based on the acceptance criteria in Equation . In order to preserve detailed balance, the momenta of the system must be reversed after acceptance or rejection of proposed moves, or the momenta must be reassigned randomly from a Boltzmann distribution after the move; in this work, we take the latter approach and randomly assign the momenta of the of the entire system after a NCMC move attempt.