As a final test, we looked at ligand 4, which also has two distinct binding modes in CDK2. The occupancies of the two binding modes have been reported to 60:40 based on electron density maps by Zundert et al. with an error bar of ∼10%. With MD/NCMC, we obtain an oc- cupancy ratio of 53:47, which is within the experimental error margin. Overall, we find that MD/NCMC significantly improves performance of transition sampling for all three ligands (2-4) which have multiple chemically distinct binding modes. Particularly, for all of these ligands, MD did not allow transitions during the 100 ns long simulations(Figure ). The binding modes are likely separated by large energy barriers, which is not easy to overcome with standard MD. Like Monte Carlo moves, the success of NCMC moves is not dependent on the height of the barriers and NCMC moves are able to overcome them. Thus, we see an enhancement in the sampling of binding modes using our MD/NCMC method.