Interactions between Endohedral Metallofullerenes and Proteins: The Gd@C(60)–Lysozyme Model

[Image: see text] Endohedral metallofullerenes (EMFs) have great potential as radioisotope carriers for nuclear medicine and as contrast agents for X-ray and magnetic resonance imaging. EMFs have still important restrictions for their use due to low solubility in physiological environments, low biocompatibility, nonspecific cellular uptake, and a strong dependence of their peculiar properties on physiological parameters, such as pH and salt content. Conjugation of the EMFs with proteins can overcome many of these limitations. Here we investigated the thermodynamics of binding of a model EMF (Gd@C(60)) with a protein (lysozyme) that is known to act as a host for the empty fullerene. As a rule, even if the shape of an EMF is exactly the same as that of the related fullerene, the interactions with a protein are significantly different. The estimated interaction energy (ΔG(binding)) between Gd@C(60) and lysozyme is −18.7 kcal mol(–1), suggesting the possibility of using proteins as supramolecular carriers for EMFs. π–π stacking, hydrophobic interactions, surfactant-like interactions, and electrostatic interactions govern the formation of the hybrid between Gd@C(60) and lysozyme. The comparison of the energy contributions to the binding between C(60) or Gd@C(60) and lysozyme suggests that, although shape complementarity remains the driving force of the binding, the presence of electron transfer from the gadolinium atom to the carbon cage induces a charge distribution on the fullerene cage that strongly affects its interaction with the protein.