The 2018 Grand Challenge was a great learning opportunity, especially since this was the first challenge in which the majority of the dataset consisted of macrocycles of different sizes and charges. Macrocycles are difficult to model because of the presence of a large number of flexible bonds and conformational restraints. The free energy prediction component was particularly challenging because the dataset involved both macrocycles of different sizes and also a few linear ligands. Breaking macrocycles requires special approximations to get good convergences in free energy calculations . In addition to this, the active site of the BACE-1 target is also challenging in nature because of the presence of the aspartyl dyad.