The Study of Non-covalent Interactions using the Synergistic Combination of Experiment and Computation

Non-covalent interactions pervade all matter and play essential roles in both chemical and biological systems. Each individual non-covalent interaction is relatively weak (0.5 – 3 kcal mol-1); however, the accumulation of these weak forces often produces functional materials, such as enzymes, catalysts, and supramolecular architectures, with high binding affinities that dictate their specificity and efficiency. Often, the behaviors of non-covalent interactions in solution are complex, since solvation has a dramatic impact on the magnitude of binding forces. In addition, complementarity, preorganization, cooperativity, and allosteric effects observed in supramolecular systems introduce another layer of complexity in their overall binding events. Likewise, noncovalent interactions are multiplex, sophisticated, and intriguing, more than just the simple binding between positive and negative regions of a molecule. I have dedicated my graduate career in studying the role of several non-covalent interactions in enzyme-substrate recognition, design of synthetic host-guest systems, and catalysis. In all of the projects that I participated in, computation and experiment were simultaneously employed as this combination is often synergistic and complementary to each other. Altogether, each non-covalent interaction is unique, modular, and often the key feature in producing selective and efficient biological and chemical systems. Chapter One is a perspective on the importance and challenges in studying non-covalent interactions using both computation and experiment. Chapter Two describes in-depth fundamental study on arene-perfluoroarene interactions in solution. Chapters Three details the rational design of new, strong cyclophane-perfluoroarene complexes by precisely engineering arene-perfluoroarene and hydrogen bonding interactions. These two chapters were jointly advised by Prof. Ellen Sletten and Prof. Ken Houk where X-ray crystallography, synthesis, 1H NMR/fluorescence titrations, and computational modeling were simultaneously leveraged. Chapters Four to Nine highlight my contributions (advised by Prof. Ken Houk) in assessing several non-covalent interactions in silico from collaborations with other eminent chemists and biologists. Chapter Four details the density functional theory (DFT) and implicit solvation model benchmark for reproducing experimental ΔGa‘s in anion-binding host-guest systems. Chapters Five, Six, and Seven entail collaborative projects with Waters and Brustad groups (UNC Chapel Hill) and explore the role of cation-π, amide-π, and CH-π interactions in the recognition of lysine methylation (KMe3) and crotoylation (Kcr) by native enzymes using DFT calculations. In Chapter Eight, the role of halogen bonding was explored in the reductive dehalogenation mechanism by a bacterial tetrabromopyrrol debrominase (Bmp8) in collaboration with Moore group (Scripps). Lastly, Chapter Nine highlights the discovery of the light harvesting properties in anthracene-triphenylamine-based platinum(II) metallocages in collaboration with the Stang (U of Utah) and Deria (Southern Illinois U) groups