Modeling Kinetics and Thermodynamics of Guest Encapsulation into the [M(4)L(6)](12–) Supramolecular Organometallic Cage

[Image: see text] The encapsulation of molecular guests into supramolecular hosts is a complex molecular recognition process in which the guest displaces the solvent from the host cavity, while the host deforms to let the guest in. An atomistic description of the association would provide valuable insights on the physicochemical properties that guide it. This understanding may be used to design novel host assemblies with improved properties (i.e., affinities) toward a given class of guests. Molecular simulations may be conveniently used to model the association processes. It is thus of interest to establish efficient protocols to trace the encapsulation process and to predict the associated magnitudes ΔG(bind) and ΔG(bind)(⧧). Here, we report the calculation of the Gibbs energy barrier and Gibbs binding energy by means of explicit solvent molecular simulations for the [Ga(4)L(6)](12–) metallocage encapsulating a series of cationic molecules. The ΔG(bind)(⧧) for encapsulation was estimated by means of umbrella sampling simulations. The steps involved were identified, including ion-pair formation and naphthalene rotation (from L ligands of the metallocage) during the guest’s entrance. The ΔG(bind) values were computed using the attach–pull–release method. The results reveal the sensitivity of the estimates on the force field parameters, in particular on atomic charges, showing that higher accuracy is obtained when charges are derived from implicit solvent quantum chemical calculations. Correlation analysis identified some indicators for the binding affinity trends. All computed magnitudes are in very good agreement with experimental observations. This work provides, on one side, a benchmarked way to computationally model a highly charged metallocage encapsulation process. This includes a nonstandard parameterization and charge derivation procedure. On the other hand, it gives specific mechanistic information on the binding processes of [Ga(4)L(6)](12–) at the molecular level where key motions are depicted. Taken together, the study provides an interesting option for the future design of metal–organic cages.