Oxidoreductase dysfunction is becoming recognized as a major contribution to the debilitation of several common diseases that are highly complex with poor prospects for cure. Understanding the principles of function of the different classes of oxidoreductases, and their engineering tolerances and the thresholds of failure would almost certainly help in ameliorating the effects of the illnesses, by providing much needed diagnostic tools and pointing the direction to a cure. This proposal is aimed at understanding a fundamental part of many oxidoreductases, namely the delivery of electrons to and from catalytic or energy coupling sites. The PI plans to apply the consensus and generality extracted from our examination of natural redox protein construction and electron tunneling function to the design, de novo synthesis and assembly of simplified redox proteins; i.e., maquettes. By examing natural redox centers in the relatively simple stable, structurally characterized, heterogeneous peptide environment of maquettes, he hopes to describe the basic events that are coupled at equilibrium to the oxidation and reduction of common redox cofactors. Redox cofactors will be examined, both individually, and when integrated in multiple redox cofactor chain maquettes. The PI plans to activate intraprotein electron and radical transfer through these chains with light, oxygen or with electrical methods at the electrode/peptide monolayer interface. These maquettes are designed to ultimately access the kinetic factors that govern electron transfer and reveal how the equilibrium properties manifest themselves on the kinetic timescale.
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