Exploring the hydrogen bond enhanced halogen bond as a tool for biomolecular design and engineering

The field of therapeutic drug discovery continues to embrace computational design, development and optimization methods, and has been further invigorated by the development of artificial intelligence (AI) and machine learning (ML) techniques for biomolecular modeling, prediction, and docking purposes. Halogens have long been accepted as meaningful and beneficial additions to biological drug design. Due to their unique properties, halogens not only contribute lipophilicity and stability, but also binding affinity and specificity by forming noncovalent interactions, called halogen bonds (XBs), with electron rich atoms. In addition to their roles as small molecule ligand constituents, XBs have emerged as interesting and unique design tools for protein engineering purposes for augmenting function and stability. This thesis aims to demonstrate the value of the hydrogen bond enhanced halogen bond (HBeXB), a cooperative noncovalent interaction network, as a tool for biomolecular design. To accomplish this goal, we approach protein design applications as a whole by exploring nontraditional noncovalent interactions currently in protein engineering, the HBeXB in catalytic enzyme design, and the HBeXB impact in protein-ligand binding. Investigating the influence of HBeXBs on enzymatic catalysis and protein-ligand binding provides the foundation for accurately and effectively incorporating these cooperative noncovalent interactions in protein and drug design.