Heteroleptic MOCs (Fig. ) are especially attractive due to the potential to incorporate multiple functional units using different ligand scaffolds. Two main approaches towards heteroleptic M2L4 MOCs have been reported. Coordination-sphere engineering (also termed side-chain directing) exploits interactions between ligands to promote integrative self-assembly, e.g. through steric repulsion, hydrogen-bonding or ancillary coordinating groups. Clever and co-workers have pioneered geometric complementarity between ligands as an alternative strategy (Fig. ). Two ligands, one with a convergent coordination mode (L), the other divergent (L'), if appropriately size-matched, can successfully assemble to give the desired heteroleptic cage (Pd2L2L'2). Further developments to this strategy have yielded higher nuclearity systems with binary combinations of ligands, 20 and systems incorporating three or even four 22 different ligand frameworks. remains a significant challenge. Recently, chemists have begun exploring high-throughput computational approaches to aid in the design of MOC systems 23 (and rationalise properties). 24 Computational forecasting would reduce traditional trial-and-error strategies that can be especially costly and timeconsuming for structurally sophisticated assemblies. For example, by mapping ligands onto a wide range of defined topological templates (n = 3-30) and comparing their relative computed energies, Reek and co-workers were able to accurately predict the nuclearity of large PdnL2n polyhedra. We have previously demonstrated computationally-informed design in targeting isomers of Pd2L4 MOCs assembled from unsymmetrical ditopic ligands using low-cost semi-empirical methods. We have now tried to expand this approach to heteroleptic cage systems.