Non-covalent bond dissociation pathways: non-equilibrium dimers. A key factor in modeling the dynamics of ligandpocket systems is the capability of a physical model to investigate systems out of equilibrium accurately. To that end, we have considered six representative dissociation curves (i.e. F2B1, F2I1, L2B3, L2I3, SF2B2, and SF2I2) and conducted an in-depth analysis of the performance of selected computational methods: PBE0+MBD, PBE0+D4, PBE0+XDM, GFN2-xTB, DFTB3+MBD, and AMBER-GAFF2. In Fig. ), we present the averaged results (over six dimers) for the 'Delta metric' ∆ that measures the agreement between the dissociation curves of a given computational method and the LNO-CCSD(T) reference (see Fig. of the SI). Indeed, it is evident that SE and classical FF methods, which are the tools of choice for biomolecular modeling, perform notably worse than DFT methods. The ∆ values per dimer are listed in Table of the SI, with the best performing equilibrium methods PBE0+MBD and PBE0+D4 achieving smaller ∆ values. These findings are confirmed by analyzing the average error of E int w.r.t. LNO-CCSD(T) at each q, see Fig. ) (corresponding six individual plots are available in Fig. of the SI). Notably, the performance of each method shows a strong dependence on the intermolecular distance.