# Hydrogen Bonding Cavity Motifs About Metal Ions

> **NIH NIH R37** · UNIVERSITY OF CALIFORNIA-IRVINE · 2023 · $120,913

## Abstract

PROJECT SUMMARY (from current award 5 R37 GM050781-26)
The broad purpose of the research in this proposal is to understand how microenvironments
(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 microenvironments.
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.

## Key facts

- **NIH application ID:** 10796600
- **Project number:** 3R37GM050781-31S1
- **Recipient organization:** UNIVERSITY OF CALIFORNIA-IRVINE
- **Principal Investigator:** Andrew S. Borovik
- **Activity code:** R37 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2023
- **Award amount:** $120,913
- **Award type:** 3
- **Project period:** 1994-04-01 → 2025-12-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10796600

## Citation

> US National Institutes of Health, RePORTER application 10796600, Hydrogen Bonding Cavity Motifs About Metal Ions (3R37GM050781-31S1). Retrieved via AI Analytics 2026-06-24 from https://api.ai-analytics.org/grant/nih/10796600. Licensed CC0.

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