(Colorado State University. Libraries, 2012) Carter, Megan, author; Ho, P. Shing, advisor; Peersen, Olve, committee member; Ross, Eric, committee member; Kennan, Alan, committee member
The primary goal of the studies in this thesis is to derive a set of mathematical models to describe the anisotropic atomic nature of covalent bound halogens and by extension their molecular interactions. We use a DNA Holliday junctions as a experimental model system to assay the structure energy relationship of halogen bonds (X-bonds) in a complex biological environment. The first chapter of this dissertation is reserved for a review on DNA structure and the Holliday Junction in context of other DNA conformations. The conformational isomerization of engineered Holliday junctions will be established as a means to assay the energies of bromine X-bonds both in crystal and in solution. The experimental data are then used in the development of anisotropic force fields for use in the mathematical modeling of bromine halogen bonds, serving as a foundation to model all biological halogen interactions. The DNA Holliday junction experimental system is expanded to compare and contrast halogens from fluorine to iodine. This comprehensive study is used to determine the effects of polarization on the structure-energy relationship of biological X-bonds in solid state and solution phase. The culmination of the work in this thesis, in addition to previously published studies, provides a growing set of principles to guide knowledge-based application of halogens in drug design. These principles are applied to the selection of X-bond acceptors in a protein binding pocket, optimal placement of the halogen on the lead compound, and which halogen is best suited for a particular interaction.
