Rationalizing the Activity of an “Artificial Diels-Alderase”: Establishing Efficient and Accurate Protocols for Calculating Supramolecular Catalysis

Self-assembled cages have emerged as novel platforms to explore bioinspired catalysis. While many different size and shape supramolecular structures are now readily accessible, only a few are known to accelerate chemical reactions under substoichiometric 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, informed 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 detailed insight that would otherwise be difficult to obtain from experiments, providing new opportunities in the design of catalytically active supramolecular cages.