Unless otherwise noted, the simulation settings were the same as alanine-valine dipeptide system. The equilibration simulation trajectories were also used to define the dihedral regions. Kernel density estimation (KDE) was performed on the dihedral internal coordinates from the trajectory with a bandwidth of 0.5. From this, the maxima in the dihedral KDEs were identified. The maxima that the dihedral was closest to at the end of equilibration was used to determine the start of the region for that dihedral. The width of the dihedral regions was set so that these regions account for 95% of the probability density estimated by KDE. The width was calculated by first finding the total probability density contained within a maximum, and then expanding the width of the region starting at the maximum until 95% of that maximum's probability density was covered by the region. During MolDarting simulations, restraint atoms were automatically chosen from the heavy atoms within 10 angstroms of the ligand using Yank. The production MolDarting simulations for each ligand were all started in the LEDGF binding site. For each ligand, a to-tal of 4 production NCMC + MD simulations were run using BLUES. These simulation was run for 200 iterations and either 1,000, 10,000, or 50,000 NCMC steps for each iteration, with 10,000 MD steps after each iteration. We used MDTraj to analyze the proximity of the ligand to the protein before each MolDarting attempt where the ligand was within a dart, and after the MolDarting move.