One additional advantage of our method is the lack of penalty for ligand groups lying outside of regions of well-defined structural density. Since these ligand portions will be treated with the standard force field, this allows for their placement independently from the absence of density and in a way that is still physically meaningful. The per-atom application of the guidance force, however, does introduce an incentive for larger chemical groups to be positioned in regions of welldefined density in place of small groups, as observed with some of the µ-OR ligands (Fig. ). This issue can be mitigated by using low-pass filtered maps (e.g. SR17018 in Fig. vs Fig. ). This all points to the ways in which the ideal density to use for a given docking depends on the task at hand. The provided experimental density is used to create a spatial envelope in which the docking algorithm will try to place the ligand while still considering the physical scoring function. For tasks where the user largely wants to stay faithful to a known binding envelope in a given receptor (e.g. re-docking and ensemble screening), using a single density matched to that receptor appears to give the best results. For tasks requiring greater freedom to explore poses with different shapes compared to the reference density (e.g. crossdocking), the consensus density and even degraded density guidance is most useful.