Deans’ Summer Research Fellowship (DSRF) Story: Emily Wang

Author: Emily Wang

What was your major research question for the DSRF project and where do you hope this project will go?

Electron bifurcation (EB) is an elegant energy transduction mechanism evolved in some natural redox enzymes to efficiently produce biologically necessary low-potential products from high-potential reactants. To accomplish this task, the EB enzyme splits two electrons received from a donor substrate, sending one electron to a high-potential acceptor substrate to drive sending the other to a low-potential acceptor substrate. Bumpy free energy landscapes occur frequently in the structures of known bifurcators. For instance, the enzyme NADH-dependent ferredoxin-NADP+ oxidoreductase I (Nfn-1) contains an unusually high potential iron-sulfur cluster cofactor (H1) in its high-potential electron transport branch. The significance of this cofactor for efficient EB is not well-understood. In my DSRF project, I asked: what are the lessons we can learn from energetically bumpy natural bifurcators for how protein structure drives efficient bifurcation and for de novo protein design. I applied a master equation model with reservoirs to simulate EB in Nfn-1’s bumpy versus the theoretical EB scheme’s ramp-like energetic landscape. My theoretical study revealed that the high-potential H1 is key to efficient EB by suppressing electron short-circuiting for greater energy efficiency. However, suppression of short-circuiting comes at the cost of less electron flow through the bifurcating protein. Nfn-1's particular high-potential H1 bump ideally optimizes maximizing suppression of short-circuiting at minimal cost to electron flow. This effect is achieved by forming an electron blockade against short-circuiting pathways. My findings explain the chemical logic underpinning nature’s bumpy EB free energy landscapes and could inform the design of efficient synthetic bifurcators. I'm currently preparing a first-author manuscript for publication. Last month, I presented a poster on this project at a mathematical biology conference in Chicago. I am currently in Bristol, UK, attending a conference on biological electron transfer, where I will be presenting a flash talk on this project to experts in the field. There are further questions that I'm interested in exploring, but in the near term, I have a compelling story and a large portion of my manuscript drafted. I'm planning to carry this manuscript through to publication in the next few months.

What challenges did you encounter during your research and how did you work through these difficulties?

A result that I obtained using a simple physical model of bifurcation initially did not recapitulate in my simulations using the free energy landscape of Nfn-1. However, from this diversion, I realized that the metric I had created to measure electron short-circuiting contained an assumption that really obfuscated electron transfer kinetics important to my study. Thus, I constructed a new metric of short-circuiting. Then, my findings validated between the simple physical model and biological system.

What sparked your interest in this field?

I've always been fascinated by how and why Nature works at the molecular level. Demonstrations, like boiling ice water, in my high school chemistry courses led me to believe that a sound understanding of molecular mechanics holds remarkable potential for scientific innovation. I'm especially interested in how protein structure drives function. Experiences in molecular cancer biology, mathematical biology, and computational neuroscience eventually led me to the Beratan Lab, developing and applying physical chemistry models to study electron transfer in proteins. For me, the Beratan Lab ideally draws on quantitative modeling approaches to study biological applications.

Curious about DSRF?

This project was made possible through the Deans’ Summer Research Fellowship (DSRF)—a unique opportunity for rising juniors and seniors in the Trinity College of Arts & Sciences to pursue funded summer research full-time!