Thermodynamic driving forces of guest confinement in a photoswitchable cage

Photoswitchable cages that confine small guest molecules inside their cavities offer a way to control the binding/unbinding process through irradiation with light of different wavelengths. However, detailed characterization of the structural and thermodynamic consequences of photoswitching is very challenging to achieve by experiments alone. Thus, all-atom molecular dynamics (MD) simulations were carried out to gain insight into the relationship between the structure and binding affinity. Binding free energies of the B₁₂F₁₂^2- guest were obtained for all photochemically accessible forms of a photoswitchable dithienylethene (DTE) based coordination cage. The MD simulations show that successive photo-induced closure of the four individual DTE ligands that form the cage gradually decreases the binding affinity. Closure of the first ligand significantly lowers the unbinding barrier and the binding free energy, and therefore favours guest unbinding both kinetically and thermodynamically. The analysis of different enthalpy contributions to the free energy shows that binding is enthalpically unfavourable and thus is an entropy-driven process, in agreement with the experimental data. Separating the enthalpy into the contributions from electrostatic, van der Waals, and bonded interactions in the force field shows that the unfavourable binding enthalpy is due to the bonded interactions being more favourable in the dissociated state, suggesting the presence of structural strain in the bound complex. Thus, the simulations provide microscopic explanations for the experimental findings and provide a possible route towards the targeted design of switchable nanocontainers with modified binding properties.