Non-destructive Inhibition of Metallofullerenol Gd@C(82)(OH)(22) on WW domain: Implication on Signal Transduction Pathway

Endohedral metallofullerenol Gd@C(82)(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@C(82)(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@C(82)(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@C(82)(OH)(22) is shown to easily win the competition over PRM in occupying the active site, implying that Gd@C(82)(OH)(22) can impose a potential inhibitory effect on the WW domain. Further analyses with binding free energy landscapes reveal that Gd@C(82)(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.