# In crystallo biomimetic oxygenase chemistry within peptidic frameworks

> **NIH NIH R35** · UNIVERSITY OF ILLINOIS AT CHICAGO · 2024 · $368,110

## Abstract

Title: In crystallo biomimetic oxygenase chemistry within peptidic frameworks
Abstract:
Mononuclear non-heme Fe and Cu sites in oxygenases functionalize the highly inert C–H bonds
of substrates involved in metabolism, natural product synthesis, and global biogeochemical
cycles, all of which directly impact human health. Despite the importance of these enzymes, the
structures and properties of many key enzymatic intermediates are not fully understood. Synthetic
analogs of the intermediates facilitate more in-depth studies, but current models have shown that
the protein environment, or lack thereof, significantly affects reactivity. Site-isolation, weak-field
ligands, and noncovalent secondary interactions are hallmarks of oxygenase active sites, but
these features are difficult to simultaneously replicate in synthetic systems. To address these
gaps, our laboratory has developed single-crystalline peptide assemblies (or “frameworks”) that
bind metals in their porous channels using amino acid residues. Our central hypothesis is that
usage of peptide-based coordinating groups allows direct comparisons between the model
system and the enzyme, while the crystalline matrix stabilizes reactive species for structure
determination by X-ray crystallography. We have reproduced the critical facial triad coordination
(2His/1-carboxylate) for non-heme Fe sites, from which we will explore the structures and
chemistry of the fleeting high-valent intermediates relevant to the enzyme mechanism. The Cu
versions of these frameworks are also appropriate models for the active site of particulate
methane monooxygenase (pMMO), whose active site has been long-debated and recently
postulated to be a single Cu site bound to a 2His/Asp ligand set. Given the modularity and ease
of peptide synthesis, we will tune the structures of these sites to obtain detailed structure-function
correlations that will illuminate how protein environments elicit remarkable inorganic reactivity.
The outcomes of this research are expected to fill in key gaps in the mechanism of these enzymes
and inform the design of mechanism-based therapeutics, as well as catalysts for pharmaceutical
synthesis, water remediation, and mitigation of climate change.

## Key facts

- **NIH application ID:** 10936902
- **Project number:** 1R35GM154793-01
- **Recipient organization:** UNIVERSITY OF ILLINOIS AT CHICAGO
- **Principal Investigator:** Andy I Nguyen
- **Activity code:** R35 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $368,110
- **Award type:** 1
- **Project period:** 2024-09-10 → 2029-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10936902

## Citation

> US National Institutes of Health, RePORTER application 10936902, In crystallo biomimetic oxygenase chemistry within peptidic frameworks (1R35GM154793-01). Retrieved via AI Analytics 2026-05-21 from https://api.ai-analytics.org/grant/nih/10936902. Licensed CC0.

---

*[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*