We seek to understand the roles that protein and cofactor conformational and chemical dynamics play in biological energy transduction through the design and synthesis of peptides and small proteins. Towards this goal, we will elaborate new classes of de novo proteins that differ radically from natural photosynthetic systems and electron transfer proteins that will ultimately enable us to decipher the essential engineering criteria important for the efficient conversion of photonic energy into electrochemical potential energy. These investigations exploit de novo tetra-a-helical proteins engineered to bind donor-spacer-acceptor supermolecules and covalently linked multicofactor assemblies. We will strive to correlate structure, function, and dynamics in these systems, utilizing information derived from computational protein design, peptide synthesis, supermolecular chemistry, and ultrafast dynamical experiments that include transient optical pump / optical probe and visible pump / IR probe spectroscopies; this work will provide a deeper, more active understanding of (i) protein folding, (ii) how local electrostatic forces that surround donor, acceptor, and chromophore can be independently modulated, (iii) functional aspects of electron and proton coupled electron transfer and radical generation in proteins, and (iv) the essential dynamics of protein mediated energy transduction. ? ?

National Institute of Health (NIH)
National Institute of General Medical Sciences (NIGMS)
Research Project (R01)
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Metallobiochemistry Study Section (BMT)
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Basavappa, Ravi
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University of Pennsylvania
Schools of Arts and Sciences
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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
Ulas, Gözde; Lemmin, Thomas; Wu, Yibing et al. (2016) Designed metalloprotein stabilizes a semiquinone radical. Nat Chem 8:354-9
Polizzi, Nicholas F; Eibling, Matthew J; Perez-Aguilar, Jose Manuel et al. (2016) Photoinduced Electron Transfer Elicits a Change in the Static Dielectric Constant of a de Novo Designed Protein. J Am Chem Soc 138:2130-3
Polizzi, Nicholas F; Migliore, Agostino; Therien, Michael J et al. (2015) Defusing redox bombs? Proc Natl Acad Sci U S A 112:10821-2
Snyder, Rae Ana; Betzu, Justine; Butch, Susan E et al. (2015) Systematic Perturbations of Binuclear Non-heme Iron Sites: Structure and Dioxygen Reactivity of de Novo Due Ferri Proteins. Biochemistry 54:4637-51
Snyder, Rae Ana; Butch, Susan E; Reig, Amanda J et al. (2015) Molecular-Level Insight into the Differential Oxidase and Oxygenase Reactivities of de Novo Due Ferri Proteins. J Am Chem Soc 137:9302-14
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
Migliore, Agostino; Polizzi, Nicholas F; Therien, Michael J et al. (2014) Biochemistry and theory of proton-coupled electron transfer. Chem Rev 114:3381-465
Fry, H Christopher; Lehmann, Andreas; Sinks, Louise E et al. (2013) Computational de novo design and characterization of a protein that selectively binds a highly hyperpolarizable abiological chromophore. J Am Chem Soc 135:13914-26

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