True Dynamics of Pillararene Host-Guest Binding

J Chem Theory Comput. 2024 Dec 25. doi: 10.1021/acs.jctc.4c01361. Online ahead of print.

Abstract

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