Effective separation of hydrogen isotopes still remains one of the extremely challenging tasks in industry. Compared to the present methods that are energy-and cost-intensive, quantum sieving technology based on nanostructured materials offers a more efficient alternative approach, where metal−organic frameworks (MOFs) featuring open metal sites (OMS) can serve as an ideal platform. Herein, a combination of periodic density functional theory (DFT) with dispersive correction and high-throughput molecular simulation was employed from thermodynamic viewpoints to explore the D 2 /H 2 separation properties of 929 experimental MOFs bearing a copper-paddlewheel unit. The DFT calculations showed that there is a negligible rotational energy barrier for the molecule adsorbed at the OMS, and the movement of the Cu atoms along the Cu−Cu axis vector almost has no influence on the interaction energy. On the basis of the DFT results, a new force field with a proposed cutoff scheme was developed to accurately describe the strong isotope−OMS interaction. Under practical conditions (40 K and 1.0 bar), large-scale computational material screening demonstrated that the OMS interaction plays a more important role in highly selective materials and ignoring such interactions can lead to completely wrong identification of the most promising materials. Using the adsorption selectivity and adsorbent performance score as evaluation metrics, this work demonstrated that the materials with sql topology notably outperform many benchmark adsorbents reported so far.