title: Drug-induced conformational population shifts in topoisomerase-DNA ternary complexes.
abstract: Type II topoisomerases (TOP2) are enzymes that resolve the topological problems during DNA replication and transcription by transiently cleaving both strands and forming a cleavage complex with the DNA. Several prominent anti-cancer agents inhibit TOP2 by stabilizing the cleavage complex and engendering permanent DNA breakage. To discriminate drug binding modes in TOP2-α and TOP2-β, we applied our newly developed scoring function, dubbed AutoDock4RAP, to evaluate the binding modes of VP-16, m-AMSA, and mitoxantrone to the cleavage complexes. Docking reproduced crystallographic binding mode of VP-16 in a ternary complex of TOP2-β with root-mean-square deviation of 0.65 Å. Molecular dynamics simulation of the complex confirmed the crystallographic binding mode of VP-16 and the conformation of the residue R503. Drug-related conformational changes in R503 have been observed in ternary complexes with m-AMSA and mitoxantrone. However, the R503 rotamers in these two simulations deviate from their crystallographic conformations, indicating a relaxation dynamics from the conformations determined with the drug replacement procedure. The binding mode of VP-16 in the cleavage complex of TOP2-α was determined by the conjoint use of docking and molecular dynamics simulations, which fell within a similar binding pocket of TOP2-β cleavage complex. Our findings may facilitate more efficient design efforts targeting TOP2-α specific drugs.
authors.affiliation: Division of Mechanics, Research Center for Applied Sciences, Academia Sinica, 128 Academia Rd., Sec. 2, Nankang, Taipei 115, Taiwan. nanlan@gate.sinica.edu.tw.
authors.forename: Nan-Lan
authors.initials: NL
authors.lastname: Huang
authors.affiliation: Division of Mechanics, Research Center for Applied Sciences, Academia Sinica, 128 Academia Rd., Sec. 2, Nankang, Taipei 115, Taiwan. jlin@ntu.edu.tw.
authors.forename: Jung-Hsin
authors.initials: JH
authors.lastname: Lin
mesh_terms: D018360:Crystallography, X-Ray; D004247:DNA / Q000737:chemistry* / Q000378:metabolism*; D004250:DNA Topoisomerases, Type II / Q000737:chemistry* / Q000378:metabolism*; D015195:Drug Design; D006801:Humans; D056004:Molecular Dynamics Simulation
chemical_list: D004247:DNA; D004250:DNA Topoisomerases, Type II