title: Non-destructive inhibition of metallofullerenol Gd@C(82)(OH)(22) on WW domain: implication on signal transduction pathway.
abstract: 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.
authors.affiliation: Computational Biology Center, IBM Thomas J. Watson Research Center Yorktown Heights , NY 10598, USA.
authors.forename: Seung-gu
authors.initials: SG
authors.lastname: Kang
authors.forename: Tien
authors.initials: T
authors.lastname: Huynh
authors.forename: Ruhong
authors.initials: R
authors.lastname: Zhou
mesh_terms: D000970:Antineoplastic Agents / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D001665:Binding Sites; D003287:Contrast Media; D015536:Down-Regulation; D005109:Extracellular Matrix / Q000187:drug effects; D037741:Fullerenes / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D006801:Humans; D008024:Ligands; D020778:Matrix Metalloproteinase 2 / Q000096:biosynthesis; D020780:Matrix Metalloproteinase 9 / Q000096:biosynthesis; D056004:Molecular Dynamics Simulation; D009369:Neoplasms / Q000188:drug therapy* / Q000378:metabolism; D055232:Proline-Rich Protein Domains; D017434:Protein Structure, Tertiary; D051575:Proto-Oncogene Proteins c-yes / Q000737:chemistry* / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects
chemical_list: D000970:Antineoplastic Agents; D003287:Contrast Media; D037741:Fullerenes; D008024:Ligands; D051575:Proto-Oncogene Proteins c-yes; C489834:YES1 protein, human; D020778:Matrix Metalloproteinase 2; D020780:Matrix Metalloproteinase 9