Endohedral metallofullerenol Gd@C₈₂(OH)₂₂ has recently been shown to effectively inhibit tumor growth; however, its potential adverse bioeffects remain to be understood before its wider applications. Here, we present our study on the interaction between Gd@C₈₂(OH)₂₂ and WW domain, a representative protein domain involved in signaling and regulatory pathway, using all-atom explicit solvent molecular dynamics simulations. We find that Gd@C₈₂(OH)₂₂ has an intrinsic binding preference to the binding groove, particularly the key signature residues Y28 and W39. In its binding competition with the native ligand PRM, Gd@C₈₂(OH)₂₂ is shown to easily win the competition over PRM in occupying the active site, implying that Gd@C₈₂(OH)₂₂ can impose a potential inhibitory effect on the WW domain. Further analyses with binding free energy landscapes reveal that Gd@C₈₂(OH)₂₂ can not only directly block the binding site of the WW domain, but also effectively distract the PRM from its native binding pocket.

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