Amino acid networks in enzyme catalysis

This project aims to understand and manipulate the protein machinery necessary for enzyme function, which will facilitate the development of next-generation enzymes important for industrial and biotechnological applications. Enzymes speed up and control the chemical reactions important for life, and many enzymes have found uses in a wide-range of chemical industries. Enzymes can be envisioned as nanoscale machines, which have moving parts important for their function. By learning the principles underlying these mechanical motions, researchers will be able to better engineer enzymes to speed up desired chemical reactions under desired conditions. This research will also provide scientific training opportunities to students from historically underrepresented groups. This project will integrate middle school, high school and undergraduate students into research and outreach activities, allowing unique mentoring opportunities for older students and fostering a diverse and inclusive scientific research environment.

The three-dimensional structures of enzymes are held together by networks of noncovalent interactions. This research will uncover the interaction networks important for enzyme function to provide an understanding of how these networks guide the internal motions of enzymes. The model system that will be studied is tryptophan synthase, whose alpha and beta subunits catalyze the final two steps in tryptophan amino acid biosynthesis. The interaction networks are proposed to be important both for individual enzyme function and inter-subunit communication. The networks will be delineated by a combination of protein nuclear magnetic resonance (NMR) spectroscopy, molecular dynamics (MD) simulations and bioinformatics analyses of protein sequences. The project will also manipulate these networks and enzyme function by targeting surface-exposed, network amino acid residues through mutagenesis and covalent modification. The project aims to develop general rules for engineering interaction networks in enzymes.