We further tested our protocol on six in-house macrocycles of different size using the OpenFF 2 and GAFF2 force field. For three of them, NOE distances have been measured in water, while the three others were measured in DMSO. The results are summarized in Figure . While the ensembles in water are well predicted with both force fields, two of the three ensembles in DMSO show high numbers of NOE violations. The poor results in DMSO stem likely from the larger ring size combined with the aromatic rings within the macrocycle. From the NMR structure solution (determined using NAMFIS ), we find that these two molecules feature π-π interactions between aromatic rings in the backbone and side chain, which results in a major conformation that is not stable with a classical fixed-charge force field.