Common choices for electrostatics are AM1-BCC and RESP charge schemes, which parametrize atomic charges via molecule-specific geometric optimization, electrostatic potential (ESP) scan, and regularized least-squares fitting. Due to the time scale of inter-molecular packing involving these macrocyclic hosts, fixed-charge force fields are the mainstream description in molecular modeling. Although these macromolecular containers are commonly considered prototypical receptors compared with biomacromolecules, their dynamic behaviors and interactions with external guests could be ‘counterintuitively’ complex, featuring multi-modal binding behaviors due to the interplay between intra-molecular conformational preferences of individual components and the inter-molecular directional coordination between functional groups. The formation of host–guest interactions could be used to protect drugs that are unstable under specific conditions (e.g., light-induced damage) or improve the physiochemical properties (e.g., solubility) of pharmaceutically active molecules. The external drug-like molecules, historically recognized as guests to the host cavity, are often coordinated at the center of the host molecule. Macrocyclic hosts are employed as drug carriers and reservoirs in pharmaceutical applications. Based on the valuable observations and insightful explanations, we finally summarize some general guidelines on force field parametrization and selection in host–guest modeling. The presented investigations of force field definitions, refitting, and evaluations are unprecedently detailed. To fill this critical gap, in this paper, we profile the energetics and dynamics of four types of popular macrocycles, including cucurbiturils, pillararenes, cyclodextrins, and octa acids. However, up to now, the modeling community still lacks a general yet detailed understanding of commonly employed general-purpose force fields and the host dynamics produced by these popular selections. A balanced description of various components of interacting terms is indispensable. The formation of host–guest coordination is accompanied by the broken of host–water and host–ion interactions and sometimes also involves some conformational rearrangements of the host. The external guests are often coordinated at the center of these macromolecular containers. Macrocyclic hosts as prototypical receptors to gaseous and drug-like guests are crucial components in pharmaceutical research.

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