True Dynamics of\nPillararene Host–Guest Binding

Accurate modeling of host–guest systems is challenging\nin\nmodern computational chemistry. It requires intermolecular interaction\npatterns to be correctly described and, more importantly, the dynamic\nbehaviors of macrocyclic hosts to be accurately modeled. Pillar[<i>n</i>]arenes as a crucial family of macrocycles play a critical\nrole in host–guest chemistry and biomedical applications. The\ncarboxylated form with 6 or 7 repeating units is of high popularity\ndue to increased solubility and the compatibility between cavity size\nand drugs. While prefitted transferable force fields are dominantly\napplied in host–guest modeling, their reliability and accuracy\nfor macrocyclic hosts remain unjustified. In the current work, based\non solid numerical evidence about energetics and dynamics, we prove\nthat all transferable force fields fail to provide a correct description\nof host dynamics for the most popular carboxylated pillararenes. Therefore,\nall existing simulation reports on this host family could be biased\ndue to the unsuitability of the force-field description. Such huge\nmodeling problems do not occur in other host families that are relatively\nrigid (e.g., octa acids and cucurbiturils), highlighting the difficulties\nin modeling pillararene host–guest interactions. To pursue\nthe true picture of the pillararene dynamics and host–guest\nbinding, we fit high-quality molecule-specific parameters for the\ncarboxylated pillararene based on ab initio calculations and perform\nan exhaustive conformational search of host–guest binding modes\nwith advanced sampling techniques. We provide estimates of binding\nthermodynamics, report the true dynamic behavior of the WP6 host in\nthe bound and unbound states, and reveal a general multimodal binding\nbehavior of pillararene host–guest complexes. The current work\nserves as a critical step toward a reliable all-atom description of\npillararene host–guest coordination.