Self-assembled cages have emerged as novel platforms to explore bio-inspired catalysis. While many different size and shape supramolecular structures are now readily accessible, only a few are known to accelerate chemical reactions under sub-stoichiometric conditions. These limited examples point to a poor understanding of cage catalysis in general, limiting the ability to design new systems. Here we show that a simple and efficient density functional theory-based methodology, in-formed by explicitly solvated molecular dynamics and coupled-cluster calculations is sufficient to accurately reproduce experimental guest binding affinities (MAD = 1.9 kcal mol-1) and identify the catalytic Diels-Alder proficiencies (>80 % accuracy) of two homologous Pd2L4 metallocages with a variety of substrates. This analysis reveals how subtle structural differences in the cage framework affect binding and catalysis. These effects manifest in a smaller distortion and more favorable interaction energy for the catalytic cage compared to the inactive structure. This study gives a detailed insight that would otherwise be difficult to obtain from experiments, providing new opportunities in the design catalytically active supramolecular cages.
