Abstract
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 ΔGbind and ΔGbind⧧. Here, we report the calculation of the Gibbs energy barrier and Gibbs binding energy by means of explicit solvent molecular simulations for the [Ga4L6]12– metallocage encapsulating a series of cationic molecules. The ΔGbind⧧ 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 ΔGbind 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 [Ga4L6]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.
Highlights
Host−guest interactions play an essential role in supramolecular chemistry, a rapidly growing field of research.[1]
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
In the view to develop a computational framework able to describe the encapsulation of guest molecules into metallocages, we extended our study to the calculation of the Gibbs energy barriers of the encapsulation process
Summary
Host−guest interactions play an essential role in supramolecular chemistry, a rapidly growing field of research.[1]. The experiments on guest-exchange dynamics showed that the [Ga4L6]12− SOC deforms to enlarge an entrance for the passage of the guest, instead of transiently breaking a metal− organic ligand bond.[21,22] Previous MM3 calculations in the gas phase in combination with experiments of the guest displacement from the cage have been reported, these calculations are based on constrained searches on the potential energy surface that do not account for the full flexibility of the system.[23] uncovering the dynamics and structural fluctuations of these supramolecular assemblies in solution is fundamental to properly describe the process and for the rational design of novel cages.[24] When it comes to simulate binding processes by computational means, techniques allowing extensive conformational samplings are necessary, something unsustainable in a quantum mechanics-based framework whose computational cost is still demanding. The atomistic description of this process revealed very interesting motions in the metallocage and rearrangements in the system
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