Optimal binding sites and its corresponding binding energies between MOF-5 clusters and small guest molecules, CH 4 and CO 2 , were investigated using the ONIOM method with different levels of quantum chemical calculations. The clusters were validated using three different sizes of the MOF-5 clusters, SINGLE, DOUBLE and TRIPLE consisting of (Zn 4 O) 2 (COOCH 3 ) 10 (COO) 2 C 6 H 4 , (Zn 4 O) 3 (COOCH 3 ) 14 (COO) 4 (C 6 H 4 ) 2 and (Zn 4 O) 4 (COOCH 3 ) 18 (COO) 6 (C 6 H 4 ) 3 units, respectively. Guest molecules were assigned to lie in the configurations parallel (∥) and perpendicular (⊥) to linker (LINK) and corner (CORN) domains of the clusters. The ONIOM(MP2/6-31G ∗∗ :HF/6-31G ∗∗ ) with the corrections due to the basis set superposition errors was found to be the optimal choice for the investigation of these systems. Strong effects of cluster size were found for the CO 2 /MOF-5 complexes, i.e., the SINGLE cluster is sufficient to represent interactions with CH 4 , but the interaction with CO 2 requires the TRIPLE model. The optimal binding sites of guest molecules as well as their orientations in the cavity of the MOF-5 are CORN⊥ for both CH 4 and CO 2 with the corresponding binding energies of −3.64 and −9.27kJ/mol, respectively.