title: Molecular Recognition of Platinated DNA from Chromosomal HMGB1.
abstract: Cisplatin cures testicular and ovarian cancers with unprecedented potency. It induces its beneficial activity by covalently binding to DNA. Repair enzymes, which remove the platinated lesions from DNA, cause drug resistance. Chromosomal High Mobility Group Box proteins (HMGB) may interfere with this process by binding to platinated DNA. Using 8 μs multiple-walker well-tempered metadynamics simulations, here, we investigated the structural and the energetic determinants of one of the HMGB proteins (HMGB1A) in complex with the platinated oligonucleotide [Pt(NH3)2](2+)-d(CCUCTCTG*G*ACCTTCC)-d(GGAGAGACCTGGAAGG) (*G are platinated guanines), for which experimental structural information is available. The calculated affinity is in good agreement with experiment. The process is predicted to be enthalpy-driven, as found for other protein/DNA complexes. The Lys7 residue, whose side-chain was not resolved in the X-ray structure, is found to interact with the C4 5'-phosphate and this interaction emerges as a key facet for the molecular recognition process. In addition, our calculations provide a molecular basis for the experimentally measured decreased affinity of HMGB1A for platinated DNA, as a consequence of Cys22-Cys44 S-S bridge formation (such an oxidation cannot take place in some members of this protein family present in the testis, where the drug is particularly effective). This decrease is likely to be caused by a small yet significant rearrangement of helices H1 and H2 with consequent alteration of the Phe37 juxtaposition.
authors.affiliation: Computational Biophysics, German Research School for Simulation Sciences (joint venture of RWTH Aachen University and Forschungszentrum Jülich, Germany) , D-52425 Jülich, Germany.|Institute for Advanced Simulation IAS-5, Computational Biomedicine, Forschungszentrum Jülich , D-52425 Jülich, Germany.|Computational Biomedicine section (INM-9), Institute for Neuroscience and Medicine (INM) , 52425 Jülich, Germany.
authors.forename: Trung Hai
authors.initials: TH
authors.lastname: Nguyen
authors.affiliation: Computational Biophysics, German Research School for Simulation Sciences (joint venture of RWTH Aachen University and Forschungszentrum Jülich, Germany) , D-52425 Jülich, Germany.|Institute for Advanced Simulation IAS-5, Computational Biomedicine, Forschungszentrum Jülich , D-52425 Jülich, Germany.|Computational Biomedicine section (INM-9), Institute for Neuroscience and Medicine (INM) , 52425 Jülich, Germany.|Institute for Research in Biomedicine (IRB Barcelona), Baldiri Reixac 10, Barcelona 08028, Spain.|Joint IRB-BSC Program in Computational Biology, Barcelona, Spain.|Jülich Supercomputing Centre (JSC), Forschungszentrum Jülich, D-52425 Jülich, Germany.
authors.forename: Giulia
authors.initials: G
authors.lastname: Rossetti
authors.affiliation: Department of Chemistry, University of Bari "A. Moro" , via Edoardo Orabona 4, I-70125 Bari, Italy.
authors.forename: Fabio
authors.initials: F
authors.lastname: Arnesano
authors.affiliation: Computational Biophysics, German Research School for Simulation Sciences (joint venture of RWTH Aachen University and Forschungszentrum Jülich, Germany) , D-52425 Jülich, Germany.|Institute for Advanced Simulation IAS-5, Computational Biomedicine, Forschungszentrum Jülich , D-52425 Jülich, Germany.|Computational Biomedicine section (INM-9), Institute for Neuroscience and Medicine (INM) , 52425 Jülich, Germany.
authors.forename: Emiliano
authors.initials: E
authors.lastname: Ippoliti
authors.affiliation: Department of Chemistry, University of Bari "A. Moro" , via Edoardo Orabona 4, I-70125 Bari, Italy.
authors.forename: Giovanni
authors.initials: G
authors.lastname: Natile
authors.affiliation: Computational Biophysics, German Research School for Simulation Sciences (joint venture of RWTH Aachen University and Forschungszentrum Jülich, Germany) , D-52425 Jülich, Germany.|Institute for Advanced Simulation IAS-5, Computational Biomedicine, Forschungszentrum Jülich , D-52425 Jülich, Germany.|Computational Biomedicine section (INM-9), Institute for Neuroscience and Medicine (INM) , 52425 Jülich, Germany.
authors.forename: Paolo
authors.initials: P
authors.lastname: Carloni