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

> **NIH NIH R01** · UNIVERSITY OF CALIFORNIA, SAN DIEGO · 2024 · $316,402

## Abstract

PROJECT SUMMARY/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 been challenging or even impossible (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 nova 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 complex metal-based functions from scratch, Toward this end, we have recently developed/adapted two
powerful approaches to metalloprotein design, Metal-Centered Protein Assembly (MCPA) and MachineLearning-
guided Design of Metalloproteins (MLDM), which allow novel protein structures to be built around metal
active sites rapidly and with atomic accuracy, In the proposed research, we will further develop these "metalcentered"
protein design strategies (and establish their generalizability) by constructing de nova protein scaffolds
that will provide access to diverse metal active sites with tunable primary coordination spheres, secondarysphere
environments and global structures/properties that are difficult to attain with other protein design
strategies, We will use these protein scaffolds to build new metalloenzymes for challenging ester, amide and
phospho-ester bond hydrolysis reactions (Specific Aim 1 ), for redox reactions involving dioxygen binding and
activation (Specific Aim 2), and for abiological catalytic transformations (e,g,, hydride and carbene transfer)
(Specific Aim 3), These efforts will uncover fundamental structure-function relationships that govern diverse
metalloprotein activities, lead to better understanding of how bioinorganic complexity arises in simple protein
scaffolds, and furnish new-to-nature reactivities.

## Key facts

- **NIH application ID:** 10979074
- **Project number:** 2R01GM138884-05
- **Recipient organization:** UNIVERSITY OF CALIFORNIA, SAN DIEGO
- **Principal Investigator:** F. Akif Tezcan
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $316,402
- **Award type:** 2
- **Project period:** 2020-09-01 → 2026-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10979074

## Citation

> US National Institutes of Health, RePORTER application 10979074, Design and Evolution of Metal-Based Functions in Supramolecular Protein Scaffolds (2R01GM138884-05). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10979074. Licensed CC0.

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