# Design and Evolution of Metal-Based Functions in Supramolecular Protein Scaffolds

> **NIH NIH R01** · UNIVERSITY OF CALIFORNIA, SAN DIEGO · 2020 · $293,665

## Abstract

Metalloproteins carry out many cellular functions that are central to biology and human health. While our
knowledge of how metalloproteins function has grown immensely thanks to technological advances, we still
possess only a superficial understanding of the interplay between protein structure/dynamics and metal
coordination/reactivity. As a result, it has not yet been possible a) to predict the functional mechanism of
metalloproteins simply by looking at their structures, b) to emulate or improve upon the structures and functions
of metalloproteins by de novo design, and c) to understand how complex bioinorganic functions may have
emerged on simple peptide/protein scaffolds during natural evolution. The overarching goal of the proposed
research program is to address these three challenges by designing and constructing protein scaffolds with
increasingly more complex metal-based functions from scratch. Inspired by a hypothetical pathway for the natural
evolution of metalloproteins, we have recently developed new approaches to metalloprotein design in which
monomeric proteins are templated by metal ions to form novel supramolecular assemblies. The interfaces of
these evolutionarily naïve complexes are then engineered and evolved to create self-standing protein
architectures with complex metal-based functions. In the proposed research, we will further develop these
“metal-templated protein design” strategies by capitalizing on two new protein scaffolds developed in our lab
(DiCyt and TriCyt), which provide easy access to diverse metal coordination geometries, secondary-sphere
environments and global properties (tunable structures, oligomeric states, flexibility/rigidity) that are difficult to
attain with other protein design strategies. We will use DiCyt and TriCyt scaffolds to build metalloprotein
assemblies for stable and selective coordination of first-row transition metal ions (Specific Aim 1), for challenging
ester, amide and phospho-ester bond hydrolysis reactions (Specific Aim 2), and for redox catalytic reactions
involving dioxygen binding and activation (Specific Aim 3). These efforts will not only uncover fundamental
structure-function relationships that govern diverse metalloprotein activities, but also lead to better understanding
of how bioinorganic complexity emerges in simple protein scaffolds.

## Key facts

- **NIH application ID:** 10033233
- **Project number:** 1R01GM138884-01
- **Recipient organization:** UNIVERSITY OF CALIFORNIA, SAN DIEGO
- **Principal Investigator:** F. Akif Tezcan
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $293,665
- **Award type:** 1
- **Project period:** 2020-09-01 → 2024-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10033233

## Citation

> US National Institutes of Health, RePORTER application 10033233, Design and Evolution of Metal-Based Functions in Supramolecular Protein Scaffolds (1R01GM138884-01). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10033233. Licensed CC0.

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