Accordingly, we conducted a series of analyses that provided valuable insights into inter-and intramolecular interactions of these model protein-ligand systems from a QM perspective. Indeed, the energy decomposition of the interaction energy E int , as obtained through SAPT analysis, revealed that ligandpocket interactions are predominantly governed by dispersion and electrostatics-types of interactions often inadequately represented by MM methods. Moreover, we defined a "platinum standard" of accuracy for E int of ligand-pocket interactions by contrasting the results with the "gold standard" methods such as LNO-CCSD(T) and QMC. Notably, the previously reported disagreement between LNO-CCSD(T) and QMC for large non-covalent systems was not observed for the QUID dimers, and the overall discrepancy is small, approximately 0.3 kcal/mol. Thus, our findings demonstrated that among all studied MM and QM approaches, DFT methods such as PBE0+MBD and PBE0+D4 achieve excellent agreement with the costly LNO-CCSD(T) method in the determination of E int for equilibrium and non-equilibrium dimers. Additionally, we have identified certain limitations in widely used semiempirical (e.g., GFN2-xTB and DFTB3+MBD) and MM methods (e.g., AMBER-GAFF2 and CHARMM36) for investigating complex non-covalent motifs, which raises questions about their reliability in binding affinitny simulations. These intriguing results highlight the relevance of determining the appropriate level of theory to accurately characterize protein-ligand systems, particularly in the development of extensive QM datasets utilized in physical method benchmarking and ML-based investigations. E int (at PBE0+MBD level), enabling the electronic characterization of chemical environments within ligand-pocket motifs-a limitation of current benchmark frameworks, which primarily focus on structural and energetic features. The structural dependence of the polarizability change in dimers as a function of the monomer separation, as well as the lack of correlation between global electronic properties and E int , offers a new perspective for understanding the NCIs in protein-ligand systems.