THEORETICAL ASPECTS OF DNA SUPERCOILING

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DESCRIPTION: This project combines a variety of computational approaches (Monte Carlo and molecular dynamics simulations, energy minimization, numerical integration) with developments in elastic rod theory to examine the configurations and properties of supercoiled DNA, a topologically constrained form of the double helix subject to higher-order folding and compensatory strand twisting. Sequence-dependent features of the long, threadlike polymer are incorporated in the theory of elastic rods and treated by numerical simulations. The constraints of loop closure are treated in two different ways, one using curve fitting techniques and the other involving Euler parameters. The former approach introduces simple mathematical formulations --piecewise B-spline curves or finite Fourier series representations --that automatically satisfy the end-to-end limitations on constrained DNA. The Euler parameters are unknowns determined in the elastic rod treatment of supercoiled DNA. Both representations aid rapid optimization of chain configuration. These models are attractive in the sense that they can be compared with the known behavior of ideal systems, as well as extended to real genetic sequences with sequence dependent bending, twisting, and stretching. By combining analytical studies with computer simulations, Dr. Olson not only obtains complementary information, but also has a series of built-in checks and balances for assessing the significance of her findings. The computational results stimulate new theoretical developments, which in turn can be used to assess the validity of the calculations. The effects of the polyelectrolyte backbone and local chemical environment will be treated implicitly by introducing various pseudo-potentials between residues separated along the chain contour or by incorporating explicit external forces. The immediate goal is to describe chain configuration and properties in terms of realistic molecular models. The proposed studies may clarify the role of primary chemical features (base, sequence, sugar-phosphate backbone) and ligand binding (proteins, drugs) on the overall folding of the double helix. A second objective is to uncover structural details of supercoil-induced transitions of DNA, such as the helical unwinding implicated in biological processes. Among the scientific questions to be addressed are: (1) the role of sequence-dependent local structure and specific protein conformation on the global equilibrium structures of supercoiled DNA; (2) the effects of ligand-induced unwinding on large-scale configurational transition of spatially constrained DNAs; (3) the competing effects of multiple proteins on the overall shape and deformability of the supercoiled duplex; (4) the interplay of local and global structure in supercoiling dynamics; (5) the effect of ionic conditions on molecular shape and flexibility.