Mapping of Electron Tunneling Pathways in Proteins

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DESCRIPTION (provided by applicant): 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.