In the condensed phase, the calculation of molecular ensembles is complicated by the presence of not only intramolecular interactions but also interactions with the surrounding solvent. Small differences in the nature of the solvents can lead to dramatically different ensembles. Approaches that include explicit solvent molecules in the calculation are considered most rigorous to describe interactions of solute and solvent. However, the large number of explicit molecules comes with a steep increase in computational cost, especially for calculations that involve more expensive quantum-mechanical (QM) Hamiltonians, which scale poorly with increasing system size. Furthermore, explicit-solvent models were shown to have a lower sampling efficiency due to the additional degrees of freedom introduced by the solvent, which requires extensive sampling, and also the increase in viscosity .