title: Binding of an Indenoisoquinoline to the topoisomerase-DNA complex induces reduction of linker mobility and strengthening of protein-DNA interaction.
abstract: Long-duration comparative molecular dynamics simulations of the DNA-topoisomerase binary and DNA-topoisomerase-indenoisoquinoline ternary complexes have been carried out. The analyses demonstrated the role of the drug in conformationally stabilizing the protein-DNA interaction. In detail, the protein lips, clamping the DNA substrate, interact more tightly in the ternary complex than in the binary one. The drug also reduces the conformational space sampled by the protein linker domain through an increased interaction with the helix bundle proximal to the active site. A similar alteration of linker domain dynamics has been observed in a precedent work for topotecan but the molecular mechanisms were different if compared to those described in this work. Finally, the indenoisoquinoline keeps Lys532 far from the DNA, making it unable to participate in the religation reaction, indicating that both short- and long-range interactions contribute to the drug poisoning effect.
authors.affiliation: CASPUR Inter-University Consortium for the Application of Super-Computing for Universities and Research, Rome, Italy.
authors.forename: Giordano
authors.initials: G
authors.lastname: Mancini
authors.forename: Ilda
authors.initials: I
authors.lastname: D'Annessa
authors.forename: Andrea
authors.initials: A
authors.lastname: Coletta
authors.forename: Giovanni
authors.initials: G
authors.lastname: Chillemi
authors.forename: Yves
authors.initials: Y
authors.lastname: Pommier
authors.forename: Mark
authors.initials: M
authors.lastname: Cushman
authors.forename: Alessandro
authors.initials: A
authors.lastname: Desideri
mesh_terms: D016000:Cluster Analysis; D004247:DNA / Q000378:metabolism*; D026942:DNA Topoisomerases / Q000378:metabolism*; D006801:Humans; D006860:Hydrogen Bonding; D007192:Indenes / Q000378:metabolism*; D007546:Isoquinolines / Q000378:metabolism*; D046911:Macromolecular Substances / Q000737:chemistry / Q000378:metabolism*; D008958:Models, Molecular; D056004:Molecular Dynamics Simulation; D025341:Principal Component Analysis; D011485:Protein Binding
chemical_list: D007192:Indenes; D007546:Isoquinolines; D046911:Macromolecular Substances; D004247:DNA; D026942:DNA Topoisomerases; C039109:isoquinoline