Neuraminidase is one of the systems showing also convergence issues using the MD simulations (Fig. ), and consequently, the highest amount of deviations in both placement and ranking of water molecules when comparing the two methods. While not being the only problematic system, neuraminidase is interesting because its binding pocket is widely open with a direct access to the bulk solvent. One possi-ble explanation could be the presence abundance of charged residues (6 Arg and 1 Lys just in the near vicinity of the ligand), which in combination with the heavy atom constraints used in the MD simulations, could be responsible of creating local energy minima hindering the sampling performance. No convergence improvement was found by running longer MD simulations (100 ns triplicates) (Fig ). Because of these characteristics and the availability of multiple holo and apo experimentally determined structures (including mutants), this target is discussed more in detail.