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. Multidentate ligands will be developed that create rigid organic structures around metal ions. These ligands place hydrogen bond (H-bond) donors or acceptors proximal to the metal centers, forming specific microenvironments. One distinguishing attribute of these systems is that site-specific modulations in structure can be readily accomplished, in order to evaluate correlations with reactivity. A focus of this research is consideration of dioxygen binding and activation by metal complexes - processes linked directly 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 to desire functions. Results from structural biology show that H-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. It is still unclear, even in biomolecules, how non-covalent interactions are able to influence metal-mediated processes. Investigations into these effects require basic reactivity and mechanistic studies in which the effects of single components can be analyzed individually. We have developed synthetic H-bonding systems whereby control of the molecular components that define the structure around the metal ion is obtained;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 incorporate the exquisite control of reactivity characteristic of metalloenzymes.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
5R01GM050781-19
Application #
8018070
Study Section
Macromolecular Structure and Function A Study Section (MSFA)
Program Officer
Anderson, Vernon
Project Start
1994-04-01
Project End
2011-12-31
Budget Start
2011-01-01
Budget End
2011-12-31
Support Year
19
Fiscal Year
2011
Total Cost
$256,230
Indirect Cost
Name
University of California Irvine
Department
Chemistry
Type
Schools of Arts and Sciences
DUNS #
046705849
City
Irvine
State
CA
Country
United States
Zip Code
92697
Hill, Ethan A; Weitz, Andrew C; Onderko, Elizabeth et al. (2016) Reactivity of an Fe(IV)-Oxo Complex with Protons and Oxidants. J Am Chem Soc 138:13143-13146
Mann, Samuel I; Heinisch, Tillmann; Weitz, Andrew C et al. (2016) Modular Artificial Cupredoxins. J Am Chem Soc 138:9073-6
Mallin, Hendrik; Hestericová, 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
Lau, Nathanael; Ziller, Joseph W; Borovik, A S (2015) Sulfonamido tripods: tuning redox potentials via ligand modifications. Polyhedron 85:777-782
Cook, Sarah A; Borovik, A S (2015) Molecular designs for controlling the local environments around metal ions. Acc Chem Res 48:2407-14
Gupta, Rupal; Taguchi, Taketo; Lassalle-Kaiser, Benedikt et al. (2015) High-spin Mn-oxo complexes and their relevance to the oxygen-evolving complex within photosystem II. Proc Natl Acad Sci U S A 112:5319-24
Cook, Sarah A; Hill, Ethan A; Borovik, A S (2015) Lessons from Nature: A Bio-Inspired Approach to Molecular Design. Biochemistry 54:4167-80
Taguchi, Taketo; Stone, Kari L; Gupta, Rupal et al. (2014) Preparation and Properties of an Mn(IV-)Hydroxide Complex: Proton and Electron Transfer at a Mononuclear Manganese Site and its Relationship to the Oxygen Evolving Complex within Photosystem II. Chem Sci 5:3064-3071
Cook, Sarah A; Ziller, Joseph W; Borovik, A S (2014) Iron(II) complexes supported by sulfonamido tripodal ligands: endogenous versus exogenous substrate oxidation. Inorg Chem 53:11029-35
Sickerman, Nathaniel S; Peterson, Sonja M; Ziller, Joseph W et al. (2014) Synthesis, structure and reactivity of Fe(II/III)-NH3 complexes bearing a tripodal sulfonamido ligand. Chem Commun (Camb) 50:2515-7

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