One of the most intriguing questions about the electron transfer proteins is how the protein modifies the electron transfer properties of a given type of redox site. It is crucial to know, not only the structure of these proteins, but also the structural origins of their electron transfer properties, to gain an understanding of the molecular basis of disease and drug design. The overall goal of this research is to understand the electron transfer properties particularly the donor/acceptor energetic interactions, of electron transfer proteins at a molecular level using computer simulations and other theoretical methods. The focus is on the iron-sulfur proteins, especially the single (Fe) rubredoxins and the 2(Fe-4S) (and structurally related) ferredoxins. These ubiquitous proteins are involved in fundamental processes such as respiration and photosynthesis. In addition, the ferrodoxins are homologous to a variety of more complex enzymes. However, despite the rapidly growing number of crystal structures, the structural origins of the redox potentials for these proteins remain unclear. The premise is that they are mainly due to the electrostatic effects of the polar backbone, polar side chains and solvent. In particular, the changes in solvent accessibility upon reduction observed in MD simulations of rubredoxins can explain some of the puzzling data from mutational studies. Moreover, since the total electrostatics is the sum of many small contributions from both the protein and the solvent, rather than a few key interactions, these competing effects are often difficult to resolve from structural data alone. The approach of Dr. Ichiye is mainly based on MD simulations of the protein, which are crucial to understanding these complex phenomena, in conjunction with come supplementary electronic structure calculations of redox site analogs, thus giving a complete picture of the protein. The first two aims specific aims concern the rubredoxins and the ferredoxins and involve using MD methods to predict difference in redox potentials in mutated or homologous proteins and then to look for their structural origins, thus providing the crucial link between experimental and structures and redox potentials. The third specific aim involves using MD simulations to examine the contribution of nuclear polarization to intermolecular electron transfer in the ferrodoxins, which may be key to understanding the significance of the two redox sites, since there relatively little experimental data in this case. These three aims will lead to a fuller understanding of the proteins involved in electron transport chains and how they determine energy flow in processes such as respiration and photosynthesis.
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