Halogen bonds in biological macromolecules

Abstract

The purpose of this dissertation is to study how halogen bonds (X-bonds) affect the stability of biological macromolecules and to develop a set of empirical mathematical equations that can provide insight into the anisotropic nature of covalently bound halogens. To achieve this end, we first conducted a detailed analysis of the Protein Data Bank (PDB) to determine the prevalence of X-bonding in biological macromolecules, which allowed us to study the geometrical trends associated with X-bonding. Quantum mechanical (QM) calculations were also applied to determine how the strength of X-bonds interaction could be "tuned." The next chapter used QM calculations to help parameterize an equation that can model the anisotropic size and charge of covalently bound chlorine, bromine and iodine. The energies obtained from this equation were validated on experimentally determined X-bond data by differential scanning calorimetry (DSC) in DNA holiday junctions and were found to nearly duplicate the energies obtained in the solution state experiments. In the final chapter, we engineer X-bonds into the structure of T4 lysozyme to studying structural and thermodynamic effects of X-bonds on protein. X-bonds were introduced into the enzyme via site-specific non-canonical amino acid incorporation and then the structure and stability of the protein were assayed via X-ray crystallography and DSC, respectively. The culmination of this work has elucidated many concepts that need to be considered when trying to engineer new biologically based materials with halogens.