Activation and Inhibition of Biological Function through Design of Novel Protein-Ligand Interactions

Abstract

Virtually every process within a cell involves a protein. They serve as cellular workhorses carrying out functions such as catalysis of essential metabolites, to regulating which genes get turned on or off, to forming the structural scaffolding to retain rigidity of a cell. Proteins form the link between the genetic information encoded in DNA to the observable phenotype of an organism. The way proteins communicate is by direct physical contact with another molecule that alters its shape and dynamics to carry out a particular function. For example, G protein-coupled receptors are membrane imbedded proteins that bind to a small molecule or peptide in the extracellular environment and translate the binding event into an internal signal to regulate processes such as heart rate and even mood. The ability to selectively modulate such fundamental systems offers huge potential with broad applications from the ability to interrogate unknown cellular mechanisms to developing therapeutics when these interactions become aberrant. The scope of this dissertation encompasses determining what properties dictate protein-ligand interactions and the application of these principles to the design of new ones. In particular, chapter 1 covers the design of a molecular switch that is turned on by small molecules. I follow this up in chapter 2 by investigating how to turn off protein function with small molecules in aberrant disease states. In chapter 3 we expand from the world of small molecule ligands to design a protein to turn off function of a protein involved in bacterial pathogenesis.