Solvent-Driven Modulation of Shuttling Dynamics in an Autonomous Chemically Fueled Information Ratchet

The performance of artificial molecular machines relies on the interplay between molecular design and environmental factors, yet how solvation shapes their energy landscapes and kinetics remains poorly understood. Here, we combine well-tempered and infrequent metadynamics to investigate equilibrium shuttling in a minimal [2]rotaxane inspired by Borsley’s fuel-driven molecular motor. By systematically varying solvent polarity and hydrogen-bonding capacity, we uncover distinct thermodynamic and kinetic regimes that govern macrocycle motion. In highly polar, hydrogen-bond-accepting media, the macrocycle adopts a symmetric distribution between binding sites, with enthalpic and entropic forces in direct competition. Conversely, in low-polarity, hydrogen-bond-donating environments, the axle undergoes a conformational collapse that entropically biases occupancy toward a single station in the absence of chemical fuel. Despite comparable free-energy barriers across conditions (9–13 kcal/mol), the transition pathways exhibit pronounced solvent-dependent asymmetries and energetic ruggedness. These findings provide a molecular-level framework for understanding how solvation dictates passive ratchet behavior and offer strategic insights for designing high-performance molecular machines tailored to complex media.