Drug metabolism, DNA damage, respiration, and photosynthesis all occur via interprotein electron-transport (ET) reactions. The basic rules governing how a protein's three-dimensional structure controls intramo/ecu/ar electron transfer rates in fixed geometries is now well established. Most biological ET, however, occurs over a range of geometries in protein-protein complexes. The goal of this proposal is to employ our understanding of the molecular control of tunneling interactions, so that we may establish predictiive methods to analyze ET rates for interprotein electron transfer. Specific proteins to be explored include the key nitrogen fixing protein nitrogenase, the transmembrane energy transducing cytochrome bC1 complex of respiration, the redox enzyme sulfite oxidase, and the cytochrome b5-myoglobin redox couple. In each of these systems, protein-protein or subunit-subunit docking over a range of geometries is an essential element of the electron-transfer process. We will combine our established ET coupling analysis with electrostatic computations of docking energetics to build quantitative descriptions of interprotein ET reactions. These studies will assist in establishing a molecular-level understanding of how geometric fluctuations associated with protein hinge motion and interprotein complex formation may impact biomedicine. For example, progress toward our basic research goal could enable the development of antibiotics that disrupt essential subunit motion in the mitochondrial electron transfer chains and might also assist in establishing an understanding of why certain point mutations lead to fatal sulfite oxidase deficiency in neonatal children.
| 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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