A Dynamic Evaluation of Cisplatin Encapsulation into Pd 2 L 4 4+ Metallacages in Solution

Coordination metallacages (MCgs) enable the design of various host structures capable of binding therapeutic guest molecules, such as cisplatin. In this study, well-tempered metadynamics (WT-MetaD) simulations were performed in explicit water and DMSO to investigate the host–guest interactions between two homoleptic Pd2L44+ cages (endo-C and endo-N), differing in the hydrophilic character of their cavities, and cisplatin. The free-energy landscape revealed that the most stable state of the MCg⊃cisplatin systems corresponds to two cisplatin molecules associated with the external MCg surface (state I), via van der Waals or H-bonding interactions, regardless of the endo-functionalization. Encapsulation of a single cisplatin molecule with a second one bound at the cage periphery (state II) is accessible in water but remains less favorable for both cages and is strongly disfavored in DMSO, consistent with experimental observations. Using alternative collective variables to probe solvent coordination, the two cages exhibit distinct hydration behavior: endo-N accommodates cisplatin together with 3–4 water molecules, whereas endo-C hosts cisplatin alone due to its more hydrophobic cavity. Across simulations, the dynamic flexibility of the cages does not substantially alter the binding states. The analysis of observed MCg⊃cisplatin adducts suggests a transient association of the drug with the cage scaffold rather than tight encapsulation within the cavity, which could explain previously reported minor NMR chemical shifts in the pyridyl protons of the cage. Overall, these results highlight the highly dynamic nature of cisplatin nanoconfinement and underscore how cavity hydrophilicity governs coencapsulation of water, with implications for designing MCgs tailored for drug-delivery applications.