# Paragons of Conformational Control in Metalloenzyme Reactivity

> **NIH NIH R35** · UNIVERSITY OF ILLINOIS AT URBANA-CHAMPAIGN · 2021 · $386,100

## Abstract

Paragons of Conformational Control in Metalloenzyme Reactivity Lisa Olshansky
Project Summary. 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 be harnessed in the development of new catalysts, bioimaging
agents, and systems for targeted drug delivery. 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 are critical to human health.

## Key facts

- **NIH application ID:** 10221737
- **Project number:** 5R35GM138138-02
- **Recipient organization:** UNIVERSITY OF ILLINOIS AT URBANA-CHAMPAIGN
- **Principal Investigator:** Lisa Olshansky
- **Activity code:** R35 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $386,100
- **Award type:** 5
- **Project period:** 2020-08-01 → 2025-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10221737

## Citation

> US National Institutes of Health, RePORTER application 10221737, Paragons of Conformational Control in Metalloenzyme Reactivity (5R35GM138138-02). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10221737. Licensed CC0.

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