Rationalizing the Solvent-Driven “Venus Flytrap” Mechanism in Argentivorous Molecules

This computational study examines the dynamic, thermodynamic, and electronic factors governing the selective “Venus flytrap” mechanism of argentivorous molecules and the different responses of Ag+ and Zn2+ in solution. Three independent 250 ps molecular dynamics replicas were performed for each of Ag+@TCA(4-OMe), Zn2+@TCA(4-OMe), and free TCA(4-OMe). Both cations approach the cyclen ring, but only Ag+ induces collective and sustained folding of the four aromatic side arms, with Ag-N coordination and cavity closure occurring as temporally coupled processes. Thermodynamic calculations in CH3CN indicate opposite conformational preferences: folded Ag+ complexes are favored over their unfolded structures by 24.31–30.52 kcal mol–1, whereas unfolded Zn2+ complexes are favored over their folded structures by 85.90–102.29 kcal mol–1. The differential solvation contribution associated with complex formation is much less favorable for Zn2+, particularly in the folded structures. Energy decomposition analysis (EDA) and EDA-NOCV indicate that Zn2+ has a stronger intrinsic metal–host interaction, dominated by orbital Zn-N coordination, whereas electrostatics is the largest attractive contribution in the Ag+ complexes. Folding increases the magnitude of ΔEint more strongly in relative terms for Ag+ than for Zn2+ (23.5% and 5.4%, respectively), mainly through electrostatic stabilization. Independent Gradient Model (IGM) and QTAIM analyses show more extensive participation of the aromatic cavity in the Ag+ series, while Voronoi deformation density (VDD) indicates more pronounced electron-density redistribution in the Zn2+ coordination region. The Ag+-selective conformational response reflects the balance between solvation, receptor adaptation, and the distinct metal–host interactions established by each cation.