Inspecting the interface native contacts without the use of a quaternary network (Figure ,D,bottom panel), it is evident that the UBA domain/Ubiquitin complex interface native contacts break which also can be observed visually in the simulations. This is not compatible with our atomistic simulations where the complex is stable over the entire 1 µs trajectory (Piana et al. have shown in longer atomistic simulations that the complex remains stable for at least 10 µs 42 ), and indicates an underestimation of the UBA domain/Ubiquitin complex stability when simulating it without applying a quaternary network. When introducing a quaternary network between the proteins using OLIVES, the interfacial native contacts are conserved, which is interesting considering that the interface is mainly of hydrophobic character with only a few hydrogen bond partners. The GoMARTINI quaternary network also reproduces the interface native contacts, albeit using a more extensive bond network than OLIVES, as seen in Figure ,A. The interface bias energy (total bias of the Gō-like model bonds using a quaternary network minus the individual protein Gō-like models without a quaternary network), amounts to -16 kcal/mol for the OLIVES model and -54 kcal/mol for the GoMARTINI model, showing that OLIVES stabilizes the complex using three times less bias energy. The experimental dissociation constant of the UBA domain/Ubiquitin complex is ≈ 57 µM, 32 corresponding to dissociation free energy of ≈ -5.7 kcal/mol at 293 K, which is difficult to reconcile with bias energies of both -16 kcal/mol for OLIVES or -54 kcal/mol for GoMARTINI. Quantitatively, it is not clear which amount of bias energy would be appropriate to obtain an accurate binding free energy. This could be investigated by calculating the complex dissociation free energy using enhanced sampling methods and comparing it to an atomistic reference, however, the correlation between experimental and simulated dissociation free energies of protein complexes is weak, even in atomistic simulations, and such a comparison is out of the scope of this introduction to the OLIVES model.