Drug metabolism, programmed cell death, DMA biosynthesis and repair, respiration, and photosynthesis all occur via electron-transport (ET) mechanisms. Theoretical and experimental advances indicate that both protein structure and dynamics control ET reaction kinetics, and that changes in the kinetics of these reactions may lead to disease states or may be used for therapeutic purposes. In the case of ET within proteins, structure and dynamics both appear to control the reaction mechanism. For inter-protein ET, minority population conformations appear to dominate the kinetics. Seminal recent experiments provide key structural and kinetic data for intra-protein and inter-protein ET that should allow us to develop a detailed understanding of the reaction mechanisms. Additional chemical modification and mutation studies are revealing details of the reaction mechanisms. Surprising rate dependencies on protein structure, docking mode, and solvent isotopes have been reported, and these observations are not anticipated by the simple static theoretical models. This proposal aims to develop molecular-level descriptions of ET within and between proteins with realistic fluctuating structures. The studies will target the influence of protein and solvent dynamics on intra-protein and inter-protein ET kinetics, with the aim of establishing rules to define how protein structure and interracial water control this kinetics. Reaching our long-term goal of developing a molecular-level understanding of how proteins control ET reaction rates should enable new strategies to disrupt or enhance redox processes;these strategies could lead to new therapeutic schemes derived from controlling the flow of electrons along essential biological electron transfer chains.
| 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 |
| 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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