After generating all conformers and selecting the representative conformers for each molecule, we proceed to optimize the molecular structures. This optimization is carried out using the DFTB3+MBD level of theory in the gas phase as well as in implicit water described by the GBSA model. Once this optimization step is complete, we obtain the final set of molecular structures for AQM-gas (gas phase) and AQM-sol (implicit water) subsets. To quantitatively analyze the impact of molecule-solvent interaction on the structure of AQM molecules, we have computed ∆R between the molecular structures stored in AQM-gas and AQM-sol. Indeed, Fig. (a) displays the size dependence of the averaged ∆R (blue dots) together with the total range of ∆R values spanned at different N (blue shadow). The results show that the structures of small molecules (N ≤ 20 atoms) present ⟨∆R⟩ < 0.1 Å, i.e., they are minimally affected by the interaction with the solvent. In contrast, when dealing with molecules with N > 40 atoms, solvent effects become significantly more pronounced, and, as a result, we observe greater deviations in the ∆R values (> 2.0 Å). These variations primarily arise from the intricate molecular configurations (mostly folded ones) that typically emerge when considering a more suitable QM approach to model large-sized molecules, i.e., DFTB3+MBD supplemented with GBSA model. A similar effect can be observed when comparing the gyration radius R g for gas-phase and solvated molecular structures, see Fig. . Notice that there also are large compounds (N ≈ 90) characterized by extensively constrained structures, which remain unaffected by the interaction with implicit water. These findings hold significant relevance in the context of advancing QM-based pipelines for the creation of datasets of molecules of pharmaceutically relevant size.