With the aim to provide a systematic investigation of QM and MM approximations, we include a wide selection of methods. First, we study DFT functionals with dispersion interactions, namely PBE0+MBD, PBE0+D4, ωB97X-D3, ωB97M-V, PBE0+XDM , M06-2X, PBE0+MBD-NL, and PBE0+TS. Second, among the SE methods we study the third-order Density Functional Tight Binding DFTB3+MBD and GFN2-xTB . From the available empirical classical FFs, we included GAFF2