# Hydrogen Bonding Cavity Motifs About Metal Ions

> **NIH NIH R37** · UNIVERSITY OF CALIFORNIA-IRVINE · 2021 · $413,332

## Abstract

The broad purpose of the research in this proposal is to understand how microenvironrnents (secondary coordination
spheres) about metal ions control function. A bio-inspired synthetic approach is utilized that incorporates principles of
molecular architecture found in the active sites of metalloproteins into synthetic systems. Multidentate ligands will be
developed that create rigid organic structures around metal ions and place hydrogen bond donors or acceptors proximal
to the metal centers, forming specific microenvironments. One distinguishing attribute of these systems is the ability to
make site-specific modifications to the structure in order to evaluate correlations between the microenvironment and
reactivity. A focus of this research is the examination of transient intermediates that are formed from the activation of
dioxygen and the oxidation of water - processes that are directly linked to the maintenance of human health and aging.
Long-term goals include developing structure-function relationships in metal-assisted oxidative catalysis.
Metalloproteins perform functions not yet achieved in synthetic systems. Our hypothesis is that the lack of control of the
secondary coordination sphere in synthetic compounds is a major obstacle in establishing the desired functions. Results
from structural biology show that hydrogen bonds within the secondary coordination spheres of metalloproteins are
instrumental in regulating function. Therefore, the function and dysfunction of health-related metalloproteins can be
understood in the context of changes in their microenvironrnents. However, it is still unclear, even in biomolecules, how
non-covalent interactions influence metal-mediated processes. Investigations into these effects require fundamental
reactivity and mechanistic studies in which the contributions of single components can be analyzed individually. We
have developed synthetic hydrogen bonding systems in which the molecular components that define the structure
around the metal ion are specifically controlled; in turn, this permits the formation of systems whose activity can be
tailored to a particular function. This ability to regulate the microenvironment allows for systematic studies into structure-
function relationships that lead to fundamental understanding of chemical processes. Ultimately, this research will
provide insights into the properties of biological catalysts and lead to new classes of synthetic catalysts that exhibit the
exquisite control over reactivity that is characteristic of metalloenzymes.
RELEVANCE (See instructions):
 Please see attached.

## Key facts

- **NIH application ID:** 9978348
- **Project number:** 4R37GM050781-29
- **Recipient organization:** UNIVERSITY OF CALIFORNIA-IRVINE
- **Principal Investigator:** Andrew S. Borovik
- **Activity code:** R37 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $413,332
- **Award type:** 4C
- **Project period:** 1994-04-01 → 2025-12-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9978348

## Citation

> US National Institutes of Health, RePORTER application 9978348, Hydrogen Bonding Cavity Motifs About Metal Ions (4R37GM050781-29). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9978348. Licensed CC0.

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