In the previous sections, we presented three examples demonstrating how JOYCE3.0 can addresses increasing levels of molecular flexibility using either harmonic functions or periodic series, while the contribution of the non-bonded intramolecular term (10) remained minimal. In fact, the only function of non-bonded interaction was preventing bad contacts between atoms laying far apart in the molecular backbone (e.g. head-to-tail or similar interactions within the alkyl chains of target III). There are, however, many cases in which a high degree of internal flexibility allows the molecule to explore a complex conformational space, often characterized by several different local minima, featuring strong and specific interactions, possibly settled between non-bonded, yet neighboring atoms. This is the case for instance of internal HBs, π-π stacking or H-π patterns. To tackle such kind of higly flexible target molecules, JOYCE 3.0 comes with an improved implementation for the parameterization of non-bonded parameters (Route II, see Methods sections), which allows the intra-molecular LJ interactions to be introduced between a carefully selected set of atoms.