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.

Public Health Relevance

Please see attached.

National Institute of Health (NIH)
National Institute of General Medical Sciences (NIGMS)
Method to Extend Research in Time (MERIT) Award (R37)
Project #
Application #
Study Section
Special Emphasis Panel (NSS)
Program Officer
Aslan, Kadir
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
University of California Irvine
Schools of Arts and Sciences
United States
Zip Code
Cook, Sarah A; Bogart, Justin A; Levi, Noam et al. (2018) Mononuclear complexes of a tridentate redox-active ligand with sulfonamido groups: structure, properties, and reactivity. Chem Sci 9:6540-6547
Weitz, Andrew C; Hill, Ethan A; Oswald, Victoria F et al. (2018) Probing Hydrogen Bonding Interactions to Iron-Oxido/Hydroxido Units by 57 Fe Nuclear Resonance Vibrational Spectroscopy. Angew Chem Int Ed Engl 57:16010-16014
Lau, Nathanael; Sano, Yohei; Ziller, Joseph W et al. (2018) Modular bimetallic complexes with a sulfonamido-based ligand. Dalton Trans 47:12362-12372
Oswald, Victoria F; Weitz, Andrew C; Biswas, Saborni et al. (2018) Manganese-Hydroxido Complexes Supported by a Urea/Phosphinic Amide Tripodal Ligand. Inorg Chem 57:13341-13350
Mann, Samuel I; Heinisch, Tillmann; Ward, Thomas R et al. (2018) Coordination chemistry within a protein host: regulation of the secondary coordination sphere. Chem Commun (Camb) 54:4413-4416
Kubin, Markus; Kern, Jan; Gul, Sheraz et al. (2017) Soft x-ray absorption spectroscopy of metalloproteins and high-valent metal-complexes at room temperature using free-electron lasers. Struct Dyn 4:054307
Lau, Nathanael; Sano, Yohei; Ziller, Joseph W et al. (2017) Terminal NiII-OH/-OH2 complexes in trigonal bipyramidal geometries derived from H2O. Polyhedron 125:179-185
Sano, Yohei; Lau, Nathanael; Weitz, Andrew C et al. (2017) Models for Unsymmetrical Active Sites in Metalloproteins: Structural, Redox, and Magnetic Properties of Bimetallic Complexes with MII-(?-OH)-FeIII Cores. Inorg Chem 56:14118-14128
Jones, Jason R; Ziller, Joseph W; Borovik, A S (2017) Modulating the Primary and Secondary Coordination Spheres within a Series of CoII-OH Complexes. Inorg Chem 56:1112-1120
Mallin, Hendrik; Hestericov√°, Martina; Reuter, Raphael et al. (2016) Library design and screening protocol for artificial metalloenzymes based on the biotin-streptavidin technology. Nat Protoc 11:835-52

Showing the most recent 10 out of 27 publications