title: A multiscale dynamic model of DNA supercoil relaxation by topoisomerase IB.
abstract: In this study, we report what we believe to be the first multiscale simulation of the dynamic relaxation of DNA supercoils by human topoisomerase IB (topo IB). We leverage our previous molecular dynamics calculations of the free energy landscape describing the interaction between a short DNA fragment and topo IB. Herein, this landscape is used to prescribe boundary conditions for a computational, elastodynamic continuum rod model of a long length of supercoiled DNA. The rod model, which accounts for the nonlinear bending, twisting, and electrostatic interaction of the (negatively charged) DNA backbone, is extended to include the hydrodynamic drag induced by the surrounding physiological buffer. Simulations for a 200-bp-long DNA supercoil in complex with topo IB reveal a relaxation timescale of ∼0.1-1.0 μs. The relaxation follows a sequence of cascading reductions in the supercoil linking number (Lk), twist (Tw), and writhe (Wr) that follow companion cascading reductions in the supercoil elastic and electrostatic energies. The novel (to our knowledge) multiscale modeling method may enable simulations of the entire experimental setup that measures DNA supercoiling and relaxation via single molecule magnetic trapping.
authors.affiliation: Department of Mechanical Engineering, Texas Tech University, Lubbock, Texas, USA.
authors.forename: Todd D
authors.initials: TD
authors.lastname: Lillian
authors.forename: Maryna
authors.initials: M
authors.lastname: Taranova
authors.forename: Jeff
authors.initials: J
authors.lastname: Wereszczynski
authors.forename: Ioan
authors.initials: I
authors.lastname: Andricioaei
authors.forename: N C
authors.initials: NC
authors.lastname: Perkins
mesh_terms: D055162:Biocatalysis; D004264:DNA Topoisomerases, Type I / Q000378:metabolism*; D004278:DNA, Superhelical / Q000737:chemistry* / Q000378:metabolism*; D006801:Humans; D056004:Molecular Dynamics Simulation; D009690:Nucleic Acid Conformation; D019415:Torque
chemical_list: D004278:DNA, Superhelical; D004264:DNA Topoisomerases, Type I; C528909:TOP1 protein, human