Comprehensive Modelling of the Self-Folding Cavitand Dynamics

The conformational equilibria and guest exchange process of a resorcin[4]arene derived self‐folding cavitand receptor have been modelled in detail by molecular dynamics simulations (MD). A multi‐timescale strategy for exploring the fluxional behavior of this system has been constructed, exploiting conventional MD and accelerated MD (aMD) techniques. The use of aMD allows the reconstruction of the folding/unfolding process of the receptor by sampling high energy barrier processes unattainable by conventional MD simulations. We obtained MD trajectories sampling events occurring at different timescales: 1) rearrangement of the directional hydrogen bond seam stabilizing the receptor, 2) folding/unfolding of the structure transiting partially open intermediates, and c) guest departure from different folding stages. Most remarkably, reweighing of the biased aMD simulations provided kinetic barriers that are in very good agreement with those determined experimentally by 1H NMR. These results constitute the first comprehensive computational characterization of the complex dynamic features of cavitand receptors. Our approach emerges as a valuable rational design tool for synthetic host‐guest systems.