Drug metabolism, programmed cell death, DNA biosynthesis and repair, respiration, and photosynthesis are familiar biological processes of critical importance to human health that rely on protein-mediated electron-transfer (ET) reaction mechanisms for their function. As such, ET pathways lie at the core of life, and the malfunction of ET pathways is an underlying cause of diseases, notably diseases triggered by oxidative stress and malfunction of the mitochondrial machinery. Since ET is a process common to all forms of life, a molecular-level understanding of ET pathways in pathogenic organisms may be exploited for therapeutic advantage as well. The long-term objective of this research is to understand, at the molecular, meso, and macro scales, how biological structure and dynamics influence crucial ET reactions. Theoretical findings from this laboratory over two decades have discovered how protein structure and dynamics can modulate ET reaction mechanisms and on the nanometer length scales, and the laboratory has established widely used methods to predict the corresponding ET rates. In the last grant period we turned our focus to charge-transport systems that function on much longer length scales, where grand challenge questions are emerging regarding ET mechanism and function on the multiple nanometer to the centimeter length scales. The research proposed here focuses on: (1) the charge hopping transport on the multiple nanometer scale associated with redox-based signaling and charge hopping that relieves oxidative stress; (2) charge transport on the micrometer scale, where the anomalous kinetic signatures discovered in multi-heme extracellular bacterial appendages will be examined; (3) transport in cable bacteria on the centimeter scale, where multi-cellular bacterial assemblies with a shared outer membrane extract energy by bridging physically between reducing and oxidizing environments, exploiting a common ET conduit that enables collaboration and a rudimentary demonstration of the benefits of multi-cellularity. A hallmark of this research program has been its close collaboration between theory and cutting-edge experiment, and this core approach will continue with intensive collaborations involving Aarhus University (Denmark), the University of Antwerp (Belgium), the University of California- Irvine (USA), and Caltech (USA).

Public Health Relevance

The motion of electron charge is central to chemical synthesis, signaling, 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 on electron transfer associated with intracellular signaling pathways (vital for cellular replication) and very long distance extracellular electron transfer pathways (used by bacteria and by centimeter long bacterial cables).

National Institute of Health (NIH)
National Institute of General Medical Sciences (NIGMS)
Research Project (R01)
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Macromolecular Structure and Function A Study Section (MSFA)
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Lyster, Peter
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Duke University
Schools of Arts and Sciences
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Teo, Ruijie D; Terai, Kiriko; Migliore, Agostino et al. (2018) Electron transfer characteristics of 2'-deoxy-2'-fluoro-arabinonucleic acid, a nucleic acid with enhanced chemical stability. Phys Chem Chem Phys 20:26063-26067
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
Keinan, Shahar; Nocek, Judith M; Hoffman, Brian M et al. (2012) Interfacial hydration, dynamics and electron transfer: multi-scale ET modeling of the transient [myoglobin, cytochrome b5] complex. Phys Chem Chem Phys 14:13881-9
Polizzi, Nicholas F; Skourtis, Spiros S; Beratan, David N (2012) Physical constraints on charge transport through bacterial nanowires. Faraday Discuss 155:43-62; discussion 103-14

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