title: Structural biology of cisplatin complexes with cellular targets: the adduct with human copper chaperone atox1 in aqueous solution.
abstract: Cisplatin is one of the most used anticancer drugs. Its cellular influx and delivery to target DNA may involve the copper chaperone Atox1 protein. Although the mode of binding is established by NMR spectroscopy measurements in solution-the Pt atom binds to Cys12 and Cys15 while retaining the two ammine groups-the structural determinants of the adduct are not known. Here a structural model by hybrid Car-Parrinello density functional theory-based QM/MM simulations is provided. The platinated site minimally modifies the fold of the protein. The calculated NMR and CD spectral properties are fully consistent with the experimental data. Our in silico/in vitro approach provides, together with previous studies, an unprecedented view into the structural biology of cisplatin-protein adducts.
authors.affiliation: Computational Biophysics, German Research School for Simulation Sciences, 52425 Jülich (Germany); Computational Biomedicine, Institute for Advanced Simulation IAS-5, Forschungszentrum Jülich, 52425 (Germany); Computational Biomedicine, Institute of Neuroscience and Medicine INM-9, Forschungszentrum Jülich, 52425 Jülich (Germany).
authors.forename: Vania
authors.initials: V
authors.lastname: Calandrini
authors.forename: Trung Hai
authors.initials: TH
authors.lastname: Nguyen
authors.forename: Fabio
authors.initials: F
authors.lastname: Arnesano
authors.forename: Angela
authors.initials: A
authors.lastname: Galliani
authors.forename: Emiliano
authors.initials: E
authors.lastname: Ippoliti
authors.forename: Paolo
authors.initials: P
authors.lastname: Carloni
authors.forename: Giovanni
authors.initials: G
authors.lastname: Natile
mesh_terms: D000970:Antineoplastic Agents / Q000737:chemistry*; D002945:Cisplatin / Q000737:chemistry*; D003300:Copper / Q000737:chemistry*; D000079922:Copper Transport Proteins; D006801:Humans; D056511:Metallochaperones / Q000235:genetics* / Q000378:metabolism*; D008958:Models, Molecular; D018832:Molecular Chaperones / Q000737:chemistry*; D011485:Protein Binding
chemical_list: C474500:ATOX1 protein, human; D000970:Antineoplastic Agents; D000079922:Copper Transport Proteins; D056511:Metallochaperones; D018832:Molecular Chaperones; D003300:Copper; D002945:Cisplatin
keywords: NMR chemical shifts; cisplatin; computer chemistry; hybrid QM/MM simulations; molecular modeling