By studying various solvents in different frameworks of the IRMOF family, we were able to test experimental rules of thumb governing MOF activation procedures. We corroborated the theory that capillary stress is the primary cause for framework collapse, but rather than resulting from the bulk surface tension of the solvent we identified the formation of mesophases in the pores as the main 325 cause. In turn, this phenomenon was caused by weak solvent-MOF attraction compared to solventsolvent attraction, predisposing the solvent to cluster within the pore spaces rather than wetting the surface of the framework. In terms of framework properties, we found good agreement with the supposition that larger pore spaces inherently lead to weaker frameworks as ΔU ‡ act increases linearly with pore diameter while thermal stability remains largely unchanged. 330 TMMC simulations therefore represent a powerful tool for predicting the successful activation of MOFs for an arbitrary activation solvent or set of conditions. Using this technique, we envisage computational screening of pressure/temperature conditions during activation, thereby facilitating both MOF discovery and process intensification for scale-up to manufacture. Finally, these methods could be combined with experimental vapour sorption to provide in-depth information about 335 framework-solvent interactions and directly investigate the key factors leading to activation-collapse.