Submission EC_RISM was a QM-based physical method . In this approach, multiple geometries were generated for each microstate using the EmbedMultipleConfs function of RDKit. These structures were pre-optimized with Amber 12 using GAFF 1.7 parameters and AM1-BCC charges with an ALPB model to represent the dielectric environment of water. Conformations with an energy of more than 20 kcal/mol than the minimum structure of that microstate were discarded and the remaining structures clustered with a structural RMSD of 0.5 Angstrom. The cluster representatives were then optimized using Gaussian 16revC01