On the Conformational Dynamics of DNA: A Perspective from Molecular Dynamics Simulations

The main focus of my dissertation is on the conformational motion of DNA, studied by applying tools from the computational chemistry field. In addition, studies of relative α- and 310 helical stabilities in peptides/mini-proteins, and a molecular flooding study of the retinoid X-receptor as part of a continuing drug design effort are presented. In molecular biology, it has been well known that sequence determines structure, and structure controls function. For proteins or DNA to work properly, the correct configuration is required. Mutations may alter the structure, which can cause malfunction. Non-mutational effects, such as a change in environment may also cause a configurational change and in turn change the functionality of the protein or DNA. Many experimental technics have been developed to investigate the structural or configurational aspects of biological systems, and molecular dynamics simulation has been proven to be a useful complementary tool to gain insights into this problem due to its ability to explore the dynamics and energetics of biomolecular processes at high spatial and time resolution. Molecular dynamics simulations are constrained by the available computational power, but several computational techniques have been developed to reduce computational costs. Also, development of hardware has helped the issue. Years of hard work on force field parameter optimization built a solid foundation for molecular dynamics simulations, so that the computational model can satisfactory describe many biochemical systems in detail. Techniques such as umbrella ix sampling and reweighting methods have allowed researchers to construct free energy landscapes to reveal the relative stabilities of each major configurational state and the free energy barriers between configurations from relatively short simulations, a process which would otherwise require many microseconds of unbiased simulations. My dissertation applies multiple advanced simulation techniques to investigate several DNA conformational problems, including the coupling between DNA bending and base flipping, the anisotropy of DNA bending, and intercalation of the dye in a Cy3 labeled DNA system. The main part of this work addressed a long standing question about DNA bending: does DNA prefer to bend toward the major or minor groove. My simulations not only answered this question, but also identified the mechanism by which the one direction is favored. Another part describes peptide/mini-protein helical transitions and studies benefiting ligand design for the retinoid X-receptor