Drug metabolism, programmed cell death, DNA biosynthesis and repair, respiration, and photosynthesis all occur via electron-transfer (ET) reaction mechanisms. As such, the malfunction of ET pathways is an underlying cause of numerous human diseases. Since ET is a process common to all forms of life, a molecular-level understanding of the ET pathways in pathogenic organisms may be exploited for therapeutic advantage as well. The long-term objective of our research is to understand, at the molecular level, how biological structure and dynamics control the rates of critical ET reactions. Theoretical progress from our laboratory over two decades has found that protein structure and dynamics determine ET reaction mechanisms and rates, and we have established useful methods to predict these rates. We have also come to understand that structured water can play an essential role in mediating electron flow. In the last grant period, we found that very long- range multi-step electron hopping establishes ET pathways in some anaerobic bacteria.
The specific aims of this proposal are: (1) to understand the mechanism that couples long-distance electron transfer, in the proximity of a water filled protein cleft, to substrate catalysi in monooxygenases, and (2) to understand a new mechanism for micron to centimeter distance charge flow in bacterial appendages. The former reactions are essential for the processing of hormones and neurotransmitters in higher eukaryotes and the latter reactions are essential for metabolism in some anaerobic bacteria. In the case of monooxygenase function, we will use theoretical methods to understand the origins of the very effective coupling of the ET reaction to catalysis, namely the close synchronization of electron delivery over long distances to the chemistry of covalent bond formation. In the case of long distance ET along bacterial charge transfer conduits, also known as bacterial nanowires, we will employ a new theoretical framework to describe flickering resonant transport, a mixed incoherent-coherent regime of ET, and will assess viable mechanisms in these fascinating micrometer-to-centimeter distance regime ET reactions. Reaching our aim of establishing molecular- level predictive theories of biological ET could lead to new strategies to address the malfunction of electron transfer pathways, to understand the origins of oxidative stress, and to disrupt the essential redox chains of pathogenic organisms. The research described here will be carried out using a combination of approaches from statistical mechanics and quantum mechanics. The hallmark of our research has been the close collaboration of our theoretical research program with cutting-edge experimental groups, and this essential strategy will continue into the next research cycle.

Public Health Relevance

The motion of electron charge is central to chemical synthesis and energy flow within our cells. Understanding the function of these charge flow pathways, at the molecular level, may lead to new strategies to combat disease associated with the malfunction of these pathways, as well as schemes to eliminate pathogenic organisms by targeting weaknesses in their charge transfer pathways. We are focusing our studies specifically on reactions associated with hormone and neurotransmitter processing and on the respiratory pathways of bacteria.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
5R01GM048043-18
Application #
8845561
Study Section
Special Emphasis Panel (ZRG1)
Program Officer
Preusch, Peter
Project Start
1993-08-01
Project End
2018-05-31
Budget Start
2015-06-01
Budget End
2016-05-31
Support Year
18
Fiscal Year
2015
Total Cost
Indirect Cost
Name
Duke University
Department
Chemistry
Type
Schools of Arts and Sciences
DUNS #
044387793
City
Durham
State
NC
Country
United States
Zip Code
27705
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Teo, Ruijie D; Smithwick, Elizabeth R; Migliore, Agostino et al. (2018) A single AT-GC exchange can modulate charge transfer-induced p53-DNA dissociation. Chem Commun (Camb) 55:206-209
Polizzi, Nicholas F; Wu, Yibing; Lemmin, Thomas et al. (2017) De novo design of a hyperstable non-natural protein-ligand complex with sub-Å accuracy. Nat Chem 9:1157-1164
Polizzi, Nicholas F; Therien, Michael J; Beratan, David N (2016) Mean First-Passage Times in Biology. Isr J Chem 56:816-824
Zheng, Lianjun; Polizzi, Nicholas F; Dave, Adarsh R et al. (2016) Where Is the Electronic Oscillator Strength? Mapping Oscillator Strength across Molecular Absorption Spectra. J Phys Chem A 120:1933-43
Polizzi, Nicholas F; Migliore, Agostino; Therien, Michael J et al. (2015) Defusing redox bombs? Proc Natl Acad Sci U S A 112:10821-2
Beratan, David N; Liu, Chaoren; Migliore, Agostino et al. (2015) Charge transfer in dynamical biosystems, or the treachery of (static) images. Acc Chem Res 48:474-81
Jiang, Nan; Kuznetsov, Aleksey; Nocek, Judith M et al. (2013) Distance-independent charge recombination kinetics in cytochrome c-cytochrome c peroxidase complexes: compensating changes in the electronic coupling and reorganization energies. J Phys Chem B 117:9129-41
Beratan, David N; Onuchic, José N (2012) Redox redux. Phys Chem Chem Phys 14:13728
Balabin, Ilya A; Hu, Xiangqian; Beratan, David N (2012) Exploring biological electron transfer pathway dynamics with the Pathways plugin for VMD. J Comput Chem 33:906-10

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