Understanding How Remote Residues Influence Enzyme Catalysis

With support from the Chemical Structure, Dynamics, and Mechanisms-A (CSDM-A) Program in the Division of Chemistry, Professor Christopher Cheatum and his group are using advanced laser spectroscopy techniques to study how distant parts of a protein affect the chemistry that occurs within the active site. This research advances the fundamental understanding of catalysis and the ways that enzymes make use of networks of protein motions in order to achieve high efficiency and selectivity.

Such understanding has the potential to support the development of new catalysts for targeted chemical reactivity, as well as the design and optimization of biocatalysts for applications in bioreactors. In addition, Prof. Cheatum and his group are working to extend the capabilities of the laser spectroscopy technique to make it more widely applicable for solving chemical and biochemical problems of broad scientific interest.

The students engaged in this research develop skills in molecular biology, computational chemistry, and laser spectroscopy that are important for applications across science and technology, thus preparing them to make critical impacts in the scientific workforce. Professor Cheatum is also engaged in high-impact outreach activities involving K-12 students, and partners with faculty at a local community college in order to involve their students in his research and to encourage those students to pursue science, technology, engineering, and mathematics (STEM) careers.

This project addresses fundamental questions about the role of the long-range protein superstructure in enzyme catalyzed reactions: How does the peripheral molecular structure around a catalytic center affect its selectivity and efficiency? How far away from the catalytic center can this influence extend? How can one identify the key residues that modulate the catalyzed reaction dynamics?

The central hypothesis of this work is that long-range networks in enzymes dynamically regulate catalysis. Two-dimensional infrared (2D IR) spectroscopy is a powerful tool for probing protein conformational distributions and dynamics, and is the primary tool the team is using to probe the dynamic effects of remote protein residues. The team is working to determine the effects of remote residues on the dynamics of the catalytic center in dihydrofolate reductase, to understand the effects of remote residues involved in the rate-promoting vibration in purine nucleoside phosphorylase, and to identify remote residues that are involved in the active-site structure and reaction dynamics in formate dehydrogenase.

Understanding how long-range interactions affect enzyme reactivity has broad impact across many disciplines. Additional broader impacts of the project include the advanced technical training of graduate, undergraduate, and community college students, as well as Prof. Cheatum’s involvement in Skype a Scientist and Data Nuggets programs to share his research with K-12 students.

This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.