Achieving Chemical Accuracy in Cyclodextrin Host–Guest Binding via Integrative Atomistic Modelling

: Cyclodextrins are amphiphilic macromolecular containers that are particularly valuable in applications ranging from biomedicine to environmental science. Despite years of development of computational techniques for cyclodextrin host-guest coordination, accurate modelling of these supramolecular systems remains challenging. In this work, an integrative computational technique is presented to solve this problem. The protocol integrates a force-field recalibration procedure, equilibrium enhanced sampling, nonequilibrium Hamiltonian switching, a work convolution algorithm, a series of finite-size corrections, and energy decomposition analysis. A large-scale survey of 222 CD host-guest systems is performed to demonstrate that the protocol enables the fast calculation of cyclodextrin host-guest binding strength without compromise in accuracy, an unbiased capture of cyclodextrin dynamics in the free CD, and the multi-modal behavior of the coordination patterns, and further the identification of the physicochemical driving force stabilizing host-guest complexes. Especially, the protocol consistently provides accurate results for various systems while conventional transferable force fields systematically fail for larger and more flexible 𝛾-CD. It thus opens new opportunities for high-throughput screening and rational design across diverse macrocyclic host families.