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 comp...