Alexandra Brown Wins Hertz Thesis Prize for Characterizing the Chemistry of Iron-Sulfur Clusters
They are ubiquitous in nature, found in humans, plants, bacteria and even within microorganisms living in deep-sea hydrothermal vents. Iron-sulfur clusters are tiny complexes of iron and sulfur atoms that play critical roles in a variety of life-sustaining chemical reactions. But studying these complex, highly reactive molecules had historically been challenging; they are hard to synthesize and can transform or degrade during experiments.
Hertz Fellow Alexandra Brown overcame those challenges by designing new molecular scaffolds that can support iron-sulfur complexes, keeping them stable so they can be characterized using an array of technologies and approaches. The method reveals new atomic details about how the complexes carry out a variety of chemistry. Her findings could contribute to new ways of performing these chemical reactions, both inside and outside living cells — with implications for manufacturing, agriculture and health.
Brown’s work, part of her Massachusetts Institute of Technology (MIT) thesis, “Coordination Chemistry of Fe–S Clusters Supported by N-Heterocyclic Carbenes,” was awarded the 2023 Hertz Thesis Prize from the Hertz Foundation. The Thesis Prize recognizes fellows with exemplary, transformative doctoral theses, and Brown joins more than 60 fellows who have been previously recognized with the award. Winners are chosen by a vibrant and committed group of volunteers, consisting of Hertz Fellows and non-fellows, who serve as Thesis Reviewers for the Hertz Prize Committee.
“This was a new direction compared to anything that anyone had done with iron-sulfur clusters in the past,” said Brown, who carried out her research under the mentorship of MIT Associate Professor of Chemistry Daniel L.M. Suess. “We really just set out to see if we could explore in this space and learned that the interactions between parts of the clusters were a lot more dynamic than we had previously known.”
Iron-sulfur clusters are most often discussed for their role in nitrogen fixation — the process by which biological enzymes incorporate nitrogen into organic molecules. These reactions are critical to moving nitrogen through ecosystems and sustaining life. Understanding how iron-sulfur clusters carry this out, as well as the other reactions they play a role in, could help researchers optimize the chemical reactions within bacteria, give new types of cells the ability to acquire nitrogen (reducing the need for nitrogen fertilizers in agriculture, for instance) or lead to ways of fixing nitrogen outside of cells.
“This was a new direction compared to anything that anyone had done with iron-sulfur clusters in the past.”
“Understanding these reactions also helps us answer some important questions about interactions between metal ions, which is important for a wide variety of emerging technologies, including quantum computing ,” said Brown.
Once Brown and her colleagues had developed the method to stabilize different iron-sulfur clusters in the lab, she turned to a diverse collection of experimental approaches to study the clusters, including determining their chemical and electronic structures when attached to other molecules. Among the findings: certain iron-sulfur clusters can bind to carbon monoxide, a reaction not previously known about.
“We didn’t expect this sort of molecule to be something we could form and isolate, and so the day I got the crystal structure of an iron-sulfur cluster bound to carbon monoxide was really surprising,” said Brown. “It opened up the door to new questions about how far we can extend this to other molecules.”
Her results also underscored how the interactions between iron and sulfur themselves dictated the kinds of chemical reactions the clusters were involved in. Tiny changes to these interactions and the exact arrangements of iron and sulfur atoms had large impacts on their chemical properties.
Through additional modeling, Brown showed how synthetic iron-sulfur clusters might be able to carry out new types of chemical reactions in a variety of settings, which would have an impact on human health, agriculture and manufacturing.
Brown added that having the Hertz Fellowship is what allowed her to pursue a project that was otherwise off the beaten path.
“It let me follow things in whatever direction they led and connected me with a lot of other people who I could learn from,” said Brown.
Brown is now pursuing a postdoctoral fellowship at Princeton University, where she is working in the lab of Todd Hyster on the directed evolution of enzymes, with the goal of giving common biological enzymes the ability to synthesize new chemicals.