In order to assess the docking performance of the method in modeling full ring flexibility, ligands were docked both by modeling the full macrocycle flexibility (flexible), and while keeping rigid only the macrocycle conformation found in the crystallographic model (rigid). This allowed us to identify complexes in which other factors (e.g., scoring function limitations, water-mediated interactions, etc.) prevented reproducing the correct conformation, as well as assess the impact of the increased search complexity induced by the ring opening, In the case of rigid redocking the best pose of the most populous cluster found was within 2 Å of the crystallographic pose in 76% (68/90) cases (Figure ). In the flexible redocking task, the success rate dropped to 53% (48/90) cases. In the rigid redocking the macrocycle conformation is known from the crystal structure, making it an inherently simpler task that not representative of the challenge of prospective dockings, when only the chemical structure is known and not its conformation. The difference in success rate between rigid and flexible redocking reflects this increased difficulty but is more representative of the task faced in docking and screening. The flexible success rate substantially improves when considering only smaller ring sizes (<15 atoms), becoming comparable to the rigid redocking success rate (59% vs 69%, n=54). This is an important aspect because these ring sizes are much more abundant in crystallographic structures, constituting more than 70% of all structures, and more relevant for drug discovery programs. The results also indicate this method comes at virtually no cost to the success rate while not requiring prior knowledge of ring conformations in most relevant situations. Selected successful flexible redocking results are shown in Figure . ). If unphysical bond geometries were produced during ring closing, these would likely lead to larger RMSDs. However, we observe no evidence of this being the case, because larger RMSD are not associated with better scores from the flexible docking. This suggests that the ring closing method does not introduce scoring aberrations.