Structural Deformations in Cucurbit[n]urils: Analysis, Host-Guest Dependence, and Automated Ellipticity Measurements using ElliptiCB[n]

Cucurbit[n]urils (CB[n]s) are cyclic macrocycles with rich host-guest chemistry and can bind a variety of guests, often with high association constants. In many cases, guest binding in CB[n]s results in structural deformations in the host to accommodate guests of different sizes and shapes. Unfortunately, measuring such deformations has remained a major challenge, with only a handful of manual estimations reported in the literature. To address this challenge and to allow for the simple measurement and analysis of CB[n] deformations both in the presence and absence of guests, we have developed the public program ElliptiCB[n], which is available on GitHub, that provides a robust and automated method for measuring the elliptical deformations in CB[n] hosts. We outline the development and validation of this approach, apply ElliptiCB[n] to measure to the ellipticity of the 1113 available CB[n] structures from the Cambridge Structural Database (CSD), and directly investigate the structural deformations of CB[5], CB[6], CB[7], CB[8], and CB[10]. We also report the general landscape of accessible CB[n] elliptical deformations and compare ellipticity distributions across CB[n] hosts and host-guest complexes. We found that in almost all cases guest binding significant impacts the distribution of host ellipticity distributions and that ellipticity distributions are dissimilar across host-guest complexes of differently sized CB[n]s. We anticipate that this work will provide not only be a useful approach for understanding of the flexibility of CB[n] hosts but will also enable future measurement and standardization of ellipticity measurements of CB[n] X-ray and/or computational data.