Protein-protein electron transfer (ET) occupies a central place in biology and chemistry. Beyond this, the underlying phenomena of protein-protein recognition and docking, which are central to almost all biological processes, are particularly amenable to study through measurements of inter-protein ET, whose steep dependence on distance/pathways acts as a unique 'filter'for probing reactive configurations in the presence of more numerous non-reactive ones. Our results indicate that (a) ET across a protein-protein interface typically is modulated by conformational conversion between and within ensembles of states with different interface structures and degrees of surface hydration, (b) ET photocycles in conformationally mobile systems provide 'clocks'against which such dynamic processes can be measured, and (c) the photocycle clocks can be used to characterize the coupling of conformation to function over timescales from picoseconds to seconds. The goal of understanding protein-protein interactions and interprotein ET has led us to recent, highly successful efforts at their control through a charge-reversal strategy for redesign of the docking interface, one result being the discovery of an interprotein singlet ET photocycle on ps-ns timescales. We propose: (i) to refine the interface redesign strategy, to apply it to new partners, and to use it to discover new systems with singlet ET photocycles;(ii) to examine conformationally-modulated ET through a tightly integrated program comprised of kinetic measurements of the variations of ET with solvent, structural characterization of dynamic complexes (NMR), and computational (Brownian Dynamics/MD/Smoluchowski equation) approaches. The three systems to be studied involve distinct interfaces: myoglobin (Mb), the vehicle for protein redesign efforts, binds to electron acceptor partner proteins primarily through electrostatic interactions;the structurally characterized complex between cytochrome c peroxidase (CcP) and cytochrome c (Cc) is primarily bound by hydrophobic interactions;[Zn;Fe] hemoglobin (Hb) hybrids exhibit a mixture of interactions at the interface between the ET- partner chains. We will test the hypothesis that, as a result, each system exhibits a distinct combination of three types of conformational control of ET: dynamic processes, conversion among conformations with different degrees of surface hydration, and/or changes in volume. We also propose to 'translate'the understanding derived from these studies to the problem of nucleotide-regulated, conformationally-linked ET in catalysis by nitrogenase.
Electron transfer between proteins is vital to the physiological processes of respiration and metabolism. Beyond this, the underlying phenomena of protein-protein recognition and docking are central to almost all biological processes that underlie human physiology and health. Our research program addresses fundamental questions of interprotein electron transfer, how it is modulated by atomic motions at the protein-protein interface, and how it might be controlled by protein redesign. It translates these findings into the realm of catalysis by the enzyme, nitrogenase.
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