Paragons of conformational control in metalloenzyme reactivity lisa olshansky project summary

The National Institute of General Medical Sciences, a component of the Department of Health and Human Services National Institutes of Health, awarded the University of Illinois $614,467 on April 1, 2026, through the Biomedical Research and Research Training program (CFDA 93.859) to develop switchable artificial metalloproteins (SWARMs) that model conformational control in metalloenzyme reactivity. The research, led by principal investigator Lisa Olshansky, combines synthetically prepared metal complexes with proteins engineered to undergo allosterically driven conformational changes, creating systems in which structural changes directly link to functional changes. The work aims to quantify thermodynamic and kinetic parameters governing metallocofactor activation, entropic regulation of radical chemistry, and mechanisms of energy conversion, with applications to biocatalyst development, bioimaging agents, and biomimetic energy conversion systems. Performance occurs in Urbana, Illinois, with a period of performance extending from April 1, 2026, through January 31, 2031. The assistance type is a Project Grant.

Recent decades have witnessed a revolution in what was once a static picture of biology. For example, the tenets of biochemistry once taught that sequence determines structure, but we now know that sequence and cellular environment determine conformational sampling. Evolutionary selection acts on dynamic rather than static features. The implications for this dynamic biochemical world permeate all aspects of human health. Therefore, IT is essential that contemporary research explore the roles, mechanisms, and structure- function paradigms at play therein. However, the complex interplay between structural changes and changes in reactivity make exploring these paradigms in natural systems incredibly challenging. At the same time, simplified synthetic models typically fail to capture the key elements of control leveraged in nature to regulate activity. My approach is to combine these tactics. By incorporating synthetically prepared metal complexes into proteins that have evolved to undergo allosterically driven conformational changes, we are preparing switchable artificial metalloproteins (swarms) that represent paragons for conformational control in metalloenzyme reactivity. By creating artificial systems in which changes in structure are directly linked to changes in function, we aim to quantify the effects of conformational control in terms of thermodynamic and kinetic parameters underlying reactivity. Ultimately, this understanding can then be harnessed in the development of new biocatalysts, bioimaging agents, and new systems for biomimetic energy conversion. Our work is poised for the exploration of key unanswered questions in enzyme catalysis, such as how allosteric binding events are converted into metallocofactor activation, or how entropic factors regulate radical chemistry, or how energy conversion occurs in mitochondrial respiratory proteins. Using a wide range of biophysical and spectroscopic methods, swarms provide a platform with which to explore all of these questions, and to examine the mechanisms of regulation underlying function and dysfunction in metalloenzyme reactivity that is critical to human health.