Ultrahigh binding affinity of a hydrocarbon guest inside cucurbit[7]uril enhanced by strong host-guest charge matching.

Cucurbit[7]uril (CB[7]) is an artificial macrocyclic molecule that can form exceptionally strong host-guest complexes with binding constants higher than that of the biotin-avidin complex. Despite notable experimental efforts, there do not exist large-scale computational investigations on finding strongly binding guests of CB[7]. Herein, we develop a computational approach based on large-scale molecular modelling to predict strongly binding hydrocarbon motifs. Our results indicate that an expanded cubane (PubChem ID 101402794) will be the most strongly binding hydrocarbon guest of CB[7] among the hundreds of thousands of hydrocarbons in the PubChem database, achieving a binding affinity significantly stronger than those reported in preceding experimental studies. Our findings highlight the important role of charge complementarity in the form of quadrupole electrostatic interactions in enabling the ultrahigh binding affinity of nonpolar guest molecules with CB[7], in addition to other known contributions such as van der Waals interactions and high-energy water release.