Mechanically-interlocked molecules (MIMs) are at the basis of artificial molecular machines and are attracting increasing interest for various applications, from catalysis to drug delivery and nanoelectronics. MIMs are composed of mechanically-interconnected molecular sub-parts that can move with respect to each other, imparting these systems innately dynamical behaviors and interesting stimuli-responsive properties. The rational design of MIMs with desired functionalities requires studying their dynamics at sub-molecular resolution and on relevant timescales, which is challenging experimentally and computationally. Here, we combine molecular dynamics and metadynamics simulations to reconstruct the thermodynamics and kinetics of different types of MIMs at atomistic resolution under different conditions. As representative case studies, we use rotaxanes and molecular shuttles substantially differing in structure, architecture, and dynamical behavior. Our computational approach provides results in optimal agreement with available experimental evidence and a direct demonstration of the critical effect of the solvent on the dynamics of the MIMs. At the same time, our simulations unveil key factors controlling the dynamics of these systems, providing submolecular-level insights into the mechanisms and kinetics of shuttling. Reconstruction of the free-energy profiles from the simulations reveals details of the conformations of macrocycles on the binding site that are difficult to access via routine experiments and precious for understanding the MIMs’ behavior, while their decomposition in enthalpic and entropic contributions unveils the mechanisms and key transitions ruling the intermolecular movements between metastable states within them. The computational framework presented herein is flexible and can be used, in principle, to study a variety of mechanically-interlocked systems.
Very minor changes: - Supporting files/info renamed everywhere Supplementary files/info - in Fig. s4 there was a FES[kcal/mol] missing in a subplot label, this has been corrected - One sentence contained a repetition, and it has been corrected/rephrased