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 y-CD. It thus opens new opportunities for high-throughput screening and rational design across diverse macrocyclic host families.