Molecular Mechanisms of Energy Conversion in Respiratory Complex I

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Elucidating molecular mechanisms of biological energy conversion is crucial both for understanding the biochemistry of the cell and for developing new biomimetic energy technologies. Complex I (NADH:ubiquinone-oxidoreductase) functions as an initial entry point for electrons in the respiratory chains of bacteria and eukaryotes. By reducing quinones (Q) in its soluble domain, Complex I couples the free energy released in the process to the translocation of protons in its membrane domain. The proton transfer across the inner mitochondrial membrane and cytoplasmic membrane of bacteria generates an electrochemical proton gradient, which is subsequently used for synthesis of ATP by FoF1-ATPase and for active transport. Remarkably, mutation of titratable residues ~200 Å away from the site of Q-reduction in Complex I, inhibits both the proton-pumping and Q reduction. Although this is thermodynamically expected for a reversible proton-coupled electron transfer (PCET) machinery, it imposes several restrictions on the coupling mechanism. To explain the principles of this long-range energy propagation in Complex I, both direct (redox-driven) and indirect (conformationally-driven) mechanisms have been suggested, but the molecular details remains elusive. In this project, we employ a broad range of state-of-the-art quantum and classical molecular simulation techniques to study molecular mechanisms of the long-range proton-coupled electron transfer catalyzed by Complex I. The computational approaches provide powerful methodologies to probe mechanistic hypothesis of complex biochemical systems, and thus to get insight in the catalytic mechanisms on a molecular level. Our molecular simulations aim to address the structure, dynamics and energetics of key catalytic steps in Complex I, thus providing complementary, but also inaccessible information to many experimental techniques. In this project we aim to elucidate (1) the energetics and dynamics of the proton transfer process in the antiporter-like membrane domain of Complex I, (2) the energetics of the electron transfer process that lead to reduction of quinones in the soluble domain of Complex I, and (3) how the redox-induced changes at the quinone site are responsible for activating the proton pump.