Owing to their small size, fragments have a propensity to bind in multiple orientations, making ABFE calculations in this context problematic. Given that GCNCMC samples binding modes naturally, affinity calculations using GCNCMC titrations eliminate the need for binding mode prediction, artificial restraints, and symmetry corrections, all of which are necessary in ABFE calculations, and each requires significant user input. Crucially, unlike ABFE, there is no need to perform more than one set of calculations per molecule.